Across three studies, the c.1427C>T (p.Thr476Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild-type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as likely pathogenic for breast cancer.
ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(49)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(15); Established risk allele(1); Uncertain significance(19); Likely benign(1)
Pathogenic(1); Likely pathogenic(15); Established risk allele(1); Uncertain significance(19); Likely benign(1)
49
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007194.4(CHEK2):c.1427C>T (p.Thr476Met)
Variation ID: 128060 Accession: VCV000128060.108
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q12.1 22: 28694066 (GRCh38) [ NCBI UCSC ] 22: 29090054 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 20, 2016 Nov 24, 2024 Oct 10, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007194.4:c.1427C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Thr476Met missense NM_001005735.2:c.1556C>T NP_001005735.1:p.Thr519Met missense NM_001257387.2:c.764C>T NP_001244316.1:p.Thr255Met missense NM_001349956.2:c.1226C>T NP_001336885.1:p.Thr409Met missense NM_145862.2:c.1340C>T NP_665861.1:p.Thr447Met missense NC_000022.11:g.28694066G>A NC_000022.10:g.29090054G>A NG_008150.2:g.52801C>T LRG_302:g.52801C>T LRG_302t1:c.1427C>T LRG_302p1:p.Thr476Met - Protein change
- T476M, T255M, T409M, T447M, T519M
- Other names
-
p.T476M:ACG>ATG
- Canonical SPDI
- NC_000022.11:28694065:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
The Genome Aggregation Database (gnomAD) 0.00032
The Genome Aggregation Database (gnomAD), exomes 0.00033
Trans-Omics for Precision Medicine (TOPMed) 0.00036
Exome Aggregation Consortium (ExAC) 0.00038
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00040
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4053 | 4109 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
|
Jan 17, 2024 | RCV000116001.34 | |
| Conflicting interpretations of pathogenicity (11) |
criteria provided, conflicting classifications
|
Oct 10, 2024 | RCV000198554.40 | |
| Conflicting interpretations of pathogenicity (15) |
criteria provided, conflicting classifications
|
Jun 24, 2024 | RCV000212465.58 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 20, 2015 | RCV000210077.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 14, 2016 | RCV000259876.9 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 14, 2016 | RCV000317389.9 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 9, 2024 | RCV000499890.21 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Aug 16, 2021 | RCV001564016.5 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Aug 19, 2021 | RCV001572627.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 26, 2023 | RCV001798351.8 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001357877.6 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
May 27, 2024 | RCV003444200.3 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV004556725.1 | |
|
CHEK2-related disorder
|
Likely pathogenic (1) |
no assertion criteria provided
|
Aug 20, 2024 | RCV004528804.2 |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Colorectal Cancer
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000437713.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
|
Likely pathogenic
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Breat Cancer
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000437714.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Across three studies, the c.1427C>T (p.Thr476Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova … (more)
Across three studies, the c.1427C>T (p.Thr476Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild-type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as likely pathogenic for breast cancer. (less)
|
|
|
Likely pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
CHEK2-Related Cancer Susceptibility
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914986.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The CHEK2 c.1427C>T (p.Thr476Met) missense variant, also referred to as c.1556C>T (p.Thr519Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. … (more)
The CHEK2 c.1427C>T (p.Thr476Met) missense variant, also referred to as c.1556C>T (p.Thr519Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Likely pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447152.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Breast carcinoma (present)
Sex: female
|
|
|
Likely pathogenic
(Jan 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449986.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 3
|
|
|
Uncertain significance
(May 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043393.3
First in ClinVar: Dec 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Oct 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 2
Affected status: unknown
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004244664.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
PS3, PM2, PM5
Secondary finding: yes
|
|
|
Established risk allele
(Nov 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186804.10
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.T476M variant (also known as c.1427C>T), located in coding exon 12 of the CHEK2 gene, results from a C to T substitution at nucleotide … (more)
The p.T476M variant (also known as c.1427C>T), located in coding exon 12 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1427. The threonine at codon 476 is replaced by methionine, an amino acid with similar properties. Recent case-control studies have reported association with breast cancer risk with odds ratios ranging from 1.35 to 1.63 (Dorling et al. N Engl J Med. 2021 02;384:428-439; Bychkovsky BL et al. JAMA Oncol. 2022 Sep). Functional studies of this alteration have reported conflicting findings. In one in vivo, yeast-based growth rate assay, this variant was indicated to be semi-functional (Delimitsou A. Hum Mutat. 2019 05;40(5):631-648). However, several other studies have reported the variant as deleterious based on kinase and DNA damage response activity (Desrichard A et al. Breast Cancer Res. 2011 Nov;13:R119; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). Another study reported this alteration as deleterious in an in vitro assay of kinase activity using bacterially expressed CHEK2, but neutral in an assay conducted in a human cell line (Kleiblova P et al Int J Cancer. 2019 10;145(7):1782-1797). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is interpreted as a moderate risk mutation, also referred to as an established risk allele. (less)
|
|
|
Likely pathogenic
(Mar 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004215851.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Uncertain significance
(Aug 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001339088.8
First in ClinVar: Jun 22, 2020 Last updated: Oct 26, 2024 |
Comment:
Variant summary: CHEK2 c.1427C>T (p.Thr476Met) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Five of … (more)
Variant summary: CHEK2 c.1427C>T (p.Thr476Met) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 238040 control chromosomes. The observed variant frequency is approximately the same as the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is benign. Additionally, this variant has been observed in 8 individuals who are reportedly cancer free at age 70 in the FLOSSIES database. In addition, co-occurrences with other pathogenic variants have been observed at our laboratory (BRCA2 c.8677C>T, p.Gln2893*; PMS2 c.2444C>T, p.Ser815Leu), providing additional supporting evidence for a benign role. c.1427C>T has been reported in the literature in individuals affected with a variety of cancers such as Breast, Ovarian, Colorectal, and Pancreatic cancers (example, Le Calvez-Kelm_2011, Angelova_2012, Susswein_2015, Hu_2016, Schuber_2019, Henn_2019, Bertelsen_2019, Lerner-Ellis_2019). For some of these cases multigenic panel screening was performed, however, in most cases, the co-occurrence information was not provided and segregation studies were not performed. In addition, Leedom_2016 reported similar frequencies for the variant in their affected (at risk) population of European descent (0.07%; 46/62392 chromosomes tested). This variant was identified in an individual who tested positive for a large deletion encompassing exon 9-15 of CHEK2 in trans in an internal specimen.These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in disruption of CHEK2 kinase activity in vitro and impairs DNA damage response in a yeast assay (example, Desrichard_2011; Roeb_2012, Delimitsou_2019), suggesting a deleterious outcome or at least a possible modifying role of the variant in carcinogenesis. The following publications have been ascertained in the context of this evaluation (PMID: 22862163, 31341520, 31398194, 27621404, 31263571, 35643632, 28944238, 30851065, 22114986, 15095295, 28495237, 30680046, 26483394, 29922827, 29368341, 21244692, 27751358, 31784482, 30128536, 28008555, 27443514, 22419737, 30426508, 26845104, 26681312, 26787654, 29945567, 28135145, Young_2016). ClinVar contains an entry for this variant (Variation ID: 128060). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(Nov 20, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and colorectal cancer, susceptibility to
Affected status: no
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266166.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Feb 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV000576430.1
First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016 |
|
|
|
Likely pathogenic
(Sep 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
GeneID Lab - Advanced Molecular Diagnostics
Accession: SCV000680448.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Number of individuals with the variant: 1
Age: 40-49 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: United States
|
|
|
Uncertain significance
(Apr 16, 2018)
|
criteria provided, single submitter
Method: research
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown,
maternal
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000778585.1 First in ClinVar: Jun 30, 2018 Last updated: Jun 30, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Mar 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448806.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Apr 12, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499649.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
|
|
|
Likely pathogenic
(Jan 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821724.3
First in ClinVar: Oct 10, 2018 Last updated: Oct 02, 2021 |
Comment:
This variation detected results in the substitution of the amino acid Threonine with Methionine at codon 476 of the CHEK2 protein. The threonine residue is … (more)
This variation detected results in the substitution of the amino acid Threonine with Methionine at codon 476 of the CHEK2 protein. The threonine residue is highly conserved among species in the Protein kinase domain of the protein and there is physiochemical difference between threonine and methionine (Grantham Score 81). This variant has been described in the international literature in individuals affected with breast and endometrial cancers (PMID: 21244692, PMID: 27443514).This variant is present in mutation databases at a low frequency (rs142763740, ExAC 0.07%). The mutation database ClinVar contains entries for this variant (Variation ID: 128060). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein, a prediction supported also by experimental studies. (PMID: 22114986, PMID: 22419737). (less)
|
|
|
Uncertain significance
(Nov 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000594113.3
First in ClinVar: Aug 28, 2017 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.1427C>T, in exon 13 that results in an amino acid change, p.Thr476Met. This sequence … (more)
DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.1427C>T, in exon 13 that results in an amino acid change, p.Thr476Met. This sequence change has been described in the gnomAD population databases with a global population frequency of 0.03% (dbSNP rs142763740); however, this variant is present in a homologous region of the CHEK2 gene and therefore population data for this region may not be reliable. The p.Thr476Met change affects a highly conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. The p.Thr476Met substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Thr476Met change has been identified in patients with a personal and/or family history of breast cancer colorectal cancer, prostate cancer, and pancreatic cancer (PMIDs: 21244692, 27443514, 28944238, 29368341, 29520813, 28008555). Additionally, a different sequence change affecting the same amino acid residue (p.Thr476Lys) has been reported in an individual affected with prostate cancer (PMID: 16835864).. Experimental studies have shown that this missense change disrupts CHEK2 kinase activity in vitro and impairs DNA damage response (PMID: 22114986, 22419737). (less)
|
|
|
Uncertain significance
(Feb 05, 2022)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537374.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.1427C>T (p.T476M) variant has been reported in individuals with breast cancer (PMID: 21244692, 30426508, 30303537, 31050813), colorectal cancer (PMID: 28944238), ovarian cancer (PMID: … (more)
The CHEK2 c.1427C>T (p.T476M) variant has been reported in individuals with breast cancer (PMID: 21244692, 30426508, 30303537, 31050813), colorectal cancer (PMID: 28944238), ovarian cancer (PMID: 30322717, 31050813), prostate cancer (PMID: 29368341, 29520813), pancreatic cancer (PMID: 29945567, 29922827) and/or renal carcinoma (PMID: 32830346). In a case-control study, the variant was reported in 83/60466 breast cancer cases and in 45/53461 controls (PMID: 33471991). This variant was observed in 62/124190 chromosomes in the European (non-Finnish) population according to the Genome Aggregation Database (PMID: 32461654). This variant has been observed in 8 individuals who are reportedly cancer free at age 70 in the FLOSSIES database. This variant has been reported in ClinVar (Variation ID: 128060). Functional studies generated conflicting results (PMID: 22114986, 22419737, 30851065, and 31050813). Based on the above information the clinical significance of this variant cannot be determined with certainty at this time. In summary, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Pathogenic
(Apr 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Institute of Human Genetics, Heidelberg University
Accession: SCV002757809.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Comment:
reported as secondary finding
Sex: female
|
|
|
Likely pathogenic
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000839455.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
|
Uncertain significance
(Aug 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556902.2
First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022 |
|
|
|
Likely pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009506.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Likely pathogenic
(Jun 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022540.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Uncertain significance
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254925.13
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 476 of the CHEK2 protein (p.Thr476Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 476 of the CHEK2 protein (p.Thr476Met). This variant is present in population databases (rs142763740, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, and/or prostate cancer (PMID: 21244692, 27443514, 28008555, 28944238, 29368341, 29520813, 31050813). ClinVar contains an entry for this variant (Variation ID: 128060). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a low probability of being pathogenic (external communication). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 22114986, 22419737, 30851065, 31050813). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Feb 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429101.4
First in ClinVar: Aug 15, 2020 Last updated: Mar 10, 2024 |
Comment:
Criteria applied: PS4_MOD,PP3
Clinical Features:
Family history of cancer (present) , Breast carcinoma (present)
Sex: female
|
|
|
Uncertain significance
(May 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV005045525.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 476 of the CHEK2 protein (p.Thr476Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 476 of the CHEK2 protein (p.Thr476Met). This variant is present in population databases (rs142763740, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, and/or prostate cancer (PMID: 21244692, 27443514, 28008555, 28944238, 29368341, 29520813, 31050813). ClinVar contains an entry for this variant (Variation ID: 128060). In addition, the in silico prediction for this alteration is inconclusive. . Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 22114986, 22419737, 30851065, 31050813). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Age: 40-49 years
Sex: female
|
|
|
Uncertain significance
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002761097.5
First in ClinVar: Dec 17, 2022 Last updated: Aug 04, 2024 |
|
|
|
Uncertain significance
(Oct 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785095.2
First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018 |
|
|
|
Uncertain significance
(Apr 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579920.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3_SUP, PS4_SUP, BS3_SUP
|
Number of individuals with the variant: 6
Sex: female
|
|
|
Likely pathogenic
(Sep 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799997.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The CHEK2 c.1427C>T; p.Thr476Met variant (rs142763740) is reported in numerous individuals with CHEK2-associated cancers (Classen 2013, Girard 2019, Hu 2018, Kamihara 2022, Le Calvez-Kelm 2011, … (more)
The CHEK2 c.1427C>T; p.Thr476Met variant (rs142763740) is reported in numerous individuals with CHEK2-associated cancers (Classen 2013, Girard 2019, Hu 2018, Kamihara 2022, Le Calvez-Kelm 2011, Lilyquist 2017, Rizzolo 2019, Sutcliffe 2020), but is also reported in individuals without cancer suggesting reduced penetrance (Girard 2019). The overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). In vitro kinase assays and in vivo DNA damage response assays with the variant protein showed a loss of kinase activity and impaired function (Delimitsou 2019, Desrichard 2011, Kleiblova 2019, Roeb 2012). However, one CHEK2-cell based assay showed no effect of the variant on protein function (Kleiblova 2019). This variant is reported by multiple laboratories in ClinVar (Variation ID: 128060). It is found in the general population with an overall allele frequency of 0.03% (83/265178 alleles) in the Genome Aggregation Database. The threonine at codon 476 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.445). Based on the currently available information, this variant is considered to be likely pathogenic. References: Classen CF et al. Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis. Hum Genet. 2013 Jul;132(7):825-41. PMID: 23552953. Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. PMID: 30851065. Desrichard A et al. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res. 2011;13(6):R119. PMID: 22114986. Girard E et al. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. Int J Cancer. 2019 Apr 15;144(8):1962-1974. PMID: 30303537. Hu C et al. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. 2018 Jun 19;319(23):2401-2409. PMID: 29922827. Kamihara J et al. Germline pathogenic variants in cancer risk genes among patients with thyroid cancer and suspected predisposition. Cancer Med. 2022 Apr;11(8):1745-1752. PMID: 35174967. Kleiblova P et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797. PMID: 31050813. Le Calvez-Kelm F et al. Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 2011 Jan 18;13(1):R6. PMID: 21244692. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Rizzolo P et al. Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. Int J Cancer. 2019 Jul 15;145(2):390-400. PMID: 30613976. Roeb W et al. Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Hum Mol Genet. 2012 Jun 15;21(12):2738-44. PMID: 22419737. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. PMID: 26484312. Sutcliffe EG et al. Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing. Cancer Genet. 2020 Aug;246-247:12-17. PMID: 32805687. (less)
|
|
|
Uncertain significance
(Jun 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601155.4
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMIDs: 32658311 (2021), 33030641 (2020), 32906215 (2020), 31050813 … (more)
In the published literature, this variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMIDs: 32658311 (2021), 33030641 (2020), 32906215 (2020), 31050813 (2019), 30287823 (2018), 28008555 (2017), 22862163 (2012), 21244692 (2011)), endometrial cancer (PMID: 27443514 (2016)), pancreatic cancer (PMID: 26845104 (2016)), colorectal cancer (PMIDs: 32658311 (2021), 28944238 (2017)), and prostate cancer (PMIDs: 32832836 (2020), 29520813 (2018)). This variant has also been reported in unaffected individuals (PMIDs: 32658311 (2021), 31050813 (2019), 30287823 (2018)). Additionally, experimental studies have reported conflicting results in this variant's impact on CHEK2 protein functions (PMIDs: 31050813 (2019), 30851065 (2019), 22419737 (2012)), 22114986 (2011)). The frequency of this variant in the general population, 0.0005 (62/124190 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Jan 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000689655.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with methionine at codon 476 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with methionine at codon 476 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have demonstrated inconsistent results. The mutant protein has shown significantly reduced kinase activity in vitro using bacteria produced protein (PMID: 22114986, 31050813), but displayed normal kinase activity in a human cell assay (PMID: 31050813, 37449874). DNA damage repair assays in yeast have shown the mutant protein to exhibit partial to complete loss of function (PMID: 22419737, 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 15095295, 21244692, 22114986, 22862163, 24595525, 25186627, 26681312, 28008555, 28495237 30426508, 32658311, 32805687, 32906215, 33030641, 36315097, 37628581), prostate cancer (PMID: 29368341, 29520813), colorectal cancer (PMID: 28008555, 28135145, 28944238, 32658311), pancreatic cancer (PMID: 26483394, 26845104 29945567), and endometrial cancer (PMID: 27443514), as well as in individuals unaffected with cancer (PMID: 32658311). A history weighting algorithm score was inconsistent with that expected for CHEK2 pathogenic mutations (Mundt, et al. poster #154, ACMG 2017). This variant has been identified in 83/265178 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has been reported in two large case-control meta analyses; this variant has been identified in 83/60383 cases and 45/53416 controls (OR=1.632, 95%CI [1.135 to 2.346]) (PMID: 33471991) and 101/73048 BC cases and 60/88658 controls (OR=2.043, 95%Ci [1.4841 to 2.8125]) (PMID: 37449874). In summary, functional studies have been inconclusive regarding the impact of this variant on protein function, and this variant has been observed in individuals affected with breast cancer as well as in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197492.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Likely pathogenic
(Jun 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149910.15
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
Case control studies suggest this variant is associated with breast cancer, although odds ratios are only modestly elevated (around 1.5 or less) (PMID: 33471991, 36136322, … (more)
Case control studies suggest this variant is associated with breast cancer, although odds ratios are only modestly elevated (around 1.5 or less) (PMID: 33471991, 36136322, 37449874); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26681312, 29368341, 21244692, 29945567, 28944238, 25186627, 26845104, 22862163, 23552953, 28008555, no PMID, 10617473, 32782288, 34028844, 32805687, 32522261, 34637943, 35220195, 32923877, 29922827, 35174967, 28888541, 26787654, 26483394, 27751358, 21901162, 28495237, 27621404, 26022348, 27443514, 15095295, 29478780, 29520813, 30128536, 31050813, 30613976, 30851065, 30426508, 24595525, 30322717, 31159747, 31784482, 30303537, 31447099, 32832836, 31263571, 31948886, 34426522, 32885271, 33193653, 32830346, 32906215, 36139606, 35441217, 35245693, 35418818, 35264596, 33471991, 22114986, 36136322, 22419737, 37449874, 19782031, 36495689, 33850299, 36368126, 36243179, 34326862, 37628581, 38075165) (less)
|
|
|
Uncertain significance
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249408.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
CHEK2: PM1, PS3:Moderate, BP4
Number of individuals with the variant: 7
|
|
|
Likely benign
(Oct 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004020185.2
First in ClinVar: Jul 29, 2023 Last updated: Nov 24, 2024 |
Comment:
This variant is considered likely benign based on an internal history weighting algorithm that has been validated and shown to have greater than 99.5% positive … (more)
This variant is considered likely benign based on an internal history weighting algorithm that has been validated and shown to have greater than 99.5% positive and negative predictive values [PMID: 25085752]. The algorithm shows this variant is not strongly associated with more severe personal and family histories of cancer which would be expected if this variant were disease causing. Curve available upon request. (less)
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953604.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036846.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553471.1 First in ClinVar: Apr 18, 2021 Last updated: Apr 18, 2021 |
Comment:
The CHEK2 p.Thr476Met variant was identified in 5 of 3910 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and non-BRCA hereditary breast … (more)
The CHEK2 p.Thr476Met variant was identified in 5 of 3910 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and non-BRCA hereditary breast cancer cases of Bulgarian and French ethnicity, and was not identified in 3244 control chromosomes from healthy individuals (Angelova 2012, Desrichard 2011, Le Calvez-Kelm 2011). However among these studies, the frequencies were not consistent and ranged from 0.01 to 0.0004. An additional large study identified the variant in 67 of 91758 proband chromsomes (freq. 0.0007) from individuals who underwent panel testing that including CHEK2 (Leedom 2016 27751358). The variant was also identified in dbSNP (ID: rs142763740) as “with likely pathogenic allele”, in ClinVar and Clinvitae databases (as likely pathogenic by GeneDx, Ambry Genetics, Illumina clinical Services, Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C, Quest Diagnostics Nichols Institute San Juan Capistrano as uncertain significance by Invitae, University of Washington Department of Laboratory Medicine and Genetic Services Laboratory, University of Chicago). The variant is further listed in the Zhejiang University database with no classification. The variant was not identified in Cosmic and MutDB databases. The same amino acid change but different nucleotide change (c.1427C>A) was observed in a patient with a clinical diagnosis of Li-Fraumeni syndrome (Sardi 2014). The variant is identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and the NHLBI GO Exome Sequencing Project in 3 of 4698 European American alleles. In addition, the variant was identified in control databases in 84 of 260146 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 6 of 22580 chromosomes (freq: 0.0003), “other” in 7 of 6276 chromosomes (freq: 0.001), Latino in 6 of 34216 chromosomes (freq: 0.0002), European Non-Finnish in 65 of 122014 chromosomes (freq: 0.0005); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. In order to evaluate mutations in all parts of the CHEK2 gene with a single biological test, an assay to evaluate CHEK2-mediated response to DNA damage was developed based on complementation of S. cerevisiae rad53 by human CHEK2. Based on growth of the strain after DNA damage, the p.Thr476Met variant was found to be damaging (Roeb 2012). The p.Thr476Met variant, which maps to the kinase domain of CHEK2, is likely to disrupt the protein function (Angelova 2012). In one study, the p.Thr476Met variant did not display kinase activity consistently and was classified as probably deleterious (Desrichard 2011). However additional functional studies are needed to determine that the p.Thr476Met variant disrupts the biological function of CHEK2. The p.Thr476 residue is conserved in in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Thr476Met variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
Number of individuals with the variant: 6
|
|
|
Likely pathogenic
(Aug 19, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Breast carcinoma
Affected status: yes
Allele origin:
germline
|
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001792256.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative
Age: 50-59 years
|
|
|
Likely pathogenic
(Aug 16, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Colon cancer
Affected status: yes
Allele origin:
germline
|
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001786717.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Colon Carcinoma
Age: 50-59 years
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807610.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001905737.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001972177.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Likely pathogenic
(Aug 20, 2024)
|
no assertion criteria provided
Method: clinical testing
|
CHEK2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806869.3
First in ClinVar: Sep 13, 2018 Last updated: Oct 08, 2024 |
Comment:
The CHEK2 c.1427C>T variant is predicted to result in the amino acid substitution p.Thr476Met. This variant has been reported in multiple individuals with breast cancer, … (more)
The CHEK2 c.1427C>T variant is predicted to result in the amino acid substitution p.Thr476Met. This variant has been reported in multiple individuals with breast cancer, with a recent study reporting an odds ratio of 1.35 (95% CI=1.03-1.77, P-value=0.03) (Table S1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Desrichard et al. 2011. PubMed ID: 22114986; Roeb et al. 2012. PubMed ID: 22419737; Angelova et al. 2012. PubMed ID: 22862163; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Schubert et al. 2019. PubMed ID: 30426508; Lerner-Ellis et al. 2020. PubMed ID: 31784482; Figure 2, Bychkovsky et al. 2022. PubMed ID: 36136322). This variant has also been reported in individuals with ovarian cancer, prostate cancer, pancreatic cancer, and colorectal cancer (Table S1, Hu et al. 2016. PubMed ID: 26483394; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table 1, Isaacsson Velho et al. 2018. PubMed ID: 29368341; Table 1, Young et al. 2018. PubMed ID: 29945567; Table S4, Bertelsen et al. 2019. PubMed ID: 31263571; Table S3, Arvai et al. 2019. PubMed ID: 31341520). In vitro and in vivo experimental studies suggest this variant results in reduced or absent kinase activity and DNA damage response (Desrichard et al. 2011. PubMed ID: 22114986; Table 1, Roeb et al. 2012. PubMed ID: 22419737; Figure 1, Kleiblova et al. 2019. PubMed ID: 31050813). An additional functional study using protein expression in yeast found that his variant results in semi-functional kinase activity (Delimitsou et al. 2019. PubMed ID: 30851065). In the gnomAD public population database this variant has been reported in up to ~0.05% of alleles in a subpopulation and has conflicting interpretations of uncertain, risk allele, and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128060/). Taken together, we interpret c.1427C>T (p.Thr476Met) as likely pathogenic. (less)
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743206.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Likely pathogenic
(Nov 24, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Li-Fraumeni syndrome 2
Affected status: yes
Allele origin:
germline
|
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004171689.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
CHEK2-related cancer predisposition
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749904.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Uncertain significance and reported on 11-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Uncertain significance and reported on 11-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Non-Hodgkin lymphoma (present) , Testicular neoplasm (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-11-27
Testing laboratory interpretation: Uncertain significance
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The CHEK2 c.1427C>T (p.Thr476Met) missense variant, also referred to as c.1556C>T (p.Thr519Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
PS3, PM2, PM5
Comment:
The p.T476M variant (also known as c.1427C>T), located in coding exon 12 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1427. The threonine at codon 476 is replaced by methionine, an amino acid with similar properties. Recent case-control studies have reported association with breast cancer risk with odds ratios ranging from 1.35 to 1.63 (Dorling et al. N Engl J Med. 2021 02;384:428-439; Bychkovsky BL et al. JAMA Oncol. 2022 Sep). Functional studies of this alteration have reported conflicting findings. In one in vivo, yeast-based growth rate assay, this variant was indicated to be semi-functional (Delimitsou A. Hum Mutat. 2019 05;40(5):631-648). However, several other studies have reported the variant as deleterious based on kinase and DNA damage response activity (Desrichard A et al. Breast Cancer Res. 2011 Nov;13:R119; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). Another study reported this alteration as deleterious in an in vitro assay of kinase activity using bacterially expressed CHEK2, but neutral in an assay conducted in a human cell line (Kleiblova P et al Int J Cancer. 2019 10;145(7):1782-1797). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is interpreted as a moderate risk mutation, also referred to as an established risk allele.
Comment:
Variant summary: CHEK2 c.1427C>T (p.Thr476Met) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 238040 control chromosomes. The observed variant frequency is approximately the same as the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is benign. Additionally, this variant has been observed in 8 individuals who are reportedly cancer free at age 70 in the FLOSSIES database. In addition, co-occurrences with other pathogenic variants have been observed at our laboratory (BRCA2 c.8677C>T, p.Gln2893*; PMS2 c.2444C>T, p.Ser815Leu), providing additional supporting evidence for a benign role. c.1427C>T has been reported in the literature in individuals affected with a variety of cancers such as Breast, Ovarian, Colorectal, and Pancreatic cancers (example, Le Calvez-Kelm_2011, Angelova_2012, Susswein_2015, Hu_2016, Schuber_2019, Henn_2019, Bertelsen_2019, Lerner-Ellis_2019). For some of these cases multigenic panel screening was performed, however, in most cases, the co-occurrence information was not provided and segregation studies were not performed. In addition, Leedom_2016 reported similar frequencies for the variant in their affected (at risk) population of European descent (0.07%; 46/62392 chromosomes tested). This variant was identified in an individual who tested positive for a large deletion encompassing exon 9-15 of CHEK2 in trans in an internal specimen.These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in disruption of CHEK2 kinase activity in vitro and impairs DNA damage response in a yeast assay (example, Desrichard_2011; Roeb_2012, Delimitsou_2019), suggesting a deleterious outcome or at least a possible modifying role of the variant in carcinogenesis. The following publications have been ascertained in the context of this evaluation (PMID: 22862163, 31341520, 31398194, 27621404, 31263571, 35643632, 28944238, 30851065, 22114986, 15095295, 28495237, 30680046, 26483394, 29922827, 29368341, 21244692, 27751358, 31784482, 30128536, 28008555, 27443514, 22419737, 30426508, 26845104, 26681312, 26787654, 29945567, 28135145, Young_2016). ClinVar contains an entry for this variant (Variation ID: 128060). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This variation detected results in the substitution of the amino acid Threonine with Methionine at codon 476 of the CHEK2 protein. The threonine residue is highly conserved among species in the Protein kinase domain of the protein and there is physiochemical difference between threonine and methionine (Grantham Score 81). This variant has been described in the international literature in individuals affected with breast and endometrial cancers (PMID: 21244692, PMID: 27443514).This variant is present in mutation databases at a low frequency (rs142763740, ExAC 0.07%). The mutation database ClinVar contains entries for this variant (Variation ID: 128060). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein, a prediction supported also by experimental studies. (PMID: 22114986, PMID: 22419737).
Comment:
DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.1427C>T, in exon 13 that results in an amino acid change, p.Thr476Met. This sequence change has been described in the gnomAD population databases with a global population frequency of 0.03% (dbSNP rs142763740); however, this variant is present in a homologous region of the CHEK2 gene and therefore population data for this region may not be reliable. The p.Thr476Met change affects a highly conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. The p.Thr476Met substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Thr476Met change has been identified in patients with a personal and/or family history of breast cancer colorectal cancer, prostate cancer, and pancreatic cancer (PMIDs: 21244692, 27443514, 28944238, 29368341, 29520813, 28008555). Additionally, a different sequence change affecting the same amino acid residue (p.Thr476Lys) has been reported in an individual affected with prostate cancer (PMID: 16835864).. Experimental studies have shown that this missense change disrupts CHEK2 kinase activity in vitro and impairs DNA damage response (PMID: 22114986, 22419737).
Comment:
reported as secondary finding
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 476 of the CHEK2 protein (p.Thr476Met). This variant is present in population databases (rs142763740, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, and/or prostate cancer (PMID: 21244692, 27443514, 28008555, 28944238, 29368341, 29520813, 31050813). ClinVar contains an entry for this variant (Variation ID: 128060). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a low probability of being pathogenic (external communication). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 22114986, 22419737, 30851065, 31050813). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Criteria applied: PS4_MOD,PP3
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 476 of the CHEK2 protein (p.Thr476Met). This variant is present in population databases (rs142763740, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, and/or prostate cancer (PMID: 21244692, 27443514, 28008555, 28944238, 29368341, 29520813, 31050813). ClinVar contains an entry for this variant (Variation ID: 128060). In addition, the in silico prediction for this alteration is inconclusive. . Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 22114986, 22419737, 30851065, 31050813). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The CHEK2 c.1427C>T; p.Thr476Met variant (rs142763740) is reported in numerous individuals with CHEK2-associated cancers (Classen 2013, Girard 2019, Hu 2018, Kamihara 2022, Le Calvez-Kelm 2011, Lilyquist 2017, Rizzolo 2019, Sutcliffe 2020), but is also reported in individuals without cancer suggesting reduced penetrance (Girard 2019). The overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). In vitro kinase assays and in vivo DNA damage response assays with the variant protein showed a loss of kinase activity and impaired function (Delimitsou 2019, Desrichard 2011, Kleiblova 2019, Roeb 2012). However, one CHEK2-cell based assay showed no effect of the variant on protein function (Kleiblova 2019). This variant is reported by multiple laboratories in ClinVar (Variation ID: 128060). It is found in the general population with an overall allele frequency of 0.03% (83/265178 alleles) in the Genome Aggregation Database. The threonine at codon 476 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.445). Based on the currently available information, this variant is considered to be likely pathogenic. References: Classen CF et al. Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis. Hum Genet. 2013 Jul;132(7):825-41. PMID: 23552953. Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. PMID: 30851065. Desrichard A et al. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res. 2011;13(6):R119. PMID: 22114986. Girard E et al. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. Int J Cancer. 2019 Apr 15;144(8):1962-1974. PMID: 30303537. Hu C et al. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. 2018 Jun 19;319(23):2401-2409. PMID: 29922827. Kamihara J et al. Germline pathogenic variants in cancer risk genes among patients with thyroid cancer and suspected predisposition. Cancer Med. 2022 Apr;11(8):1745-1752. PMID: 35174967. Kleiblova P et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797. PMID: 31050813. Le Calvez-Kelm F et al. Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 2011 Jan 18;13(1):R6. PMID: 21244692. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Rizzolo P et al. Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. Int J Cancer. 2019 Jul 15;145(2):390-400. PMID: 30613976. Roeb W et al. Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Hum Mol Genet. 2012 Jun 15;21(12):2738-44. PMID: 22419737. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. PMID: 26484312. Sutcliffe EG et al. Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing. Cancer Genet. 2020 Aug;246-247:12-17. PMID: 32805687.
Comment:
In the published literature, this variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMIDs: 32658311 (2021), 33030641 (2020), 32906215 (2020), 31050813 (2019), 30287823 (2018), 28008555 (2017), 22862163 (2012), 21244692 (2011)), endometrial cancer (PMID: 27443514 (2016)), pancreatic cancer (PMID: 26845104 (2016)), colorectal cancer (PMIDs: 32658311 (2021), 28944238 (2017)), and prostate cancer (PMIDs: 32832836 (2020), 29520813 (2018)). This variant has also been reported in unaffected individuals (PMIDs: 32658311 (2021), 31050813 (2019), 30287823 (2018)). Additionally, experimental studies have reported conflicting results in this variant's impact on CHEK2 protein functions (PMIDs: 31050813 (2019), 30851065 (2019), 22419737 (2012)), 22114986 (2011)). The frequency of this variant in the general population, 0.0005 (62/124190 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces threonine with methionine at codon 476 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have demonstrated inconsistent results. The mutant protein has shown significantly reduced kinase activity in vitro using bacteria produced protein (PMID: 22114986, 31050813), but displayed normal kinase activity in a human cell assay (PMID: 31050813, 37449874). DNA damage repair assays in yeast have shown the mutant protein to exhibit partial to complete loss of function (PMID: 22419737, 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 15095295, 21244692, 22114986, 22862163, 24595525, 25186627, 26681312, 28008555, 28495237 30426508, 32658311, 32805687, 32906215, 33030641, 36315097, 37628581), prostate cancer (PMID: 29368341, 29520813), colorectal cancer (PMID: 28008555, 28135145, 28944238, 32658311), pancreatic cancer (PMID: 26483394, 26845104 29945567), and endometrial cancer (PMID: 27443514), as well as in individuals unaffected with cancer (PMID: 32658311). A history weighting algorithm score was inconsistent with that expected for CHEK2 pathogenic mutations (Mundt, et al. poster #154, ACMG 2017). This variant has been identified in 83/265178 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has been reported in two large case-control meta analyses; this variant has been identified in 83/60383 cases and 45/53416 controls (OR=1.632, 95%CI [1.135 to 2.346]) (PMID: 33471991) and 101/73048 BC cases and 60/88658 controls (OR=2.043, 95%Ci [1.4841 to 2.8125]) (PMID: 37449874). In summary, functional studies have been inconclusive regarding the impact of this variant on protein function, and this variant has been observed in individuals affected with breast cancer as well as in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Case control studies suggest this variant is associated with breast cancer, although odds ratios are only modestly elevated (around 1.5 or less) (PMID: 33471991, 36136322, 37449874); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26681312, 29368341, 21244692, 29945567, 28944238, 25186627, 26845104, 22862163, 23552953, 28008555, no PMID, 10617473, 32782288, 34028844, 32805687, 32522261, 34637943, 35220195, 32923877, 29922827, 35174967, 28888541, 26787654, 26483394, 27751358, 21901162, 28495237, 27621404, 26022348, 27443514, 15095295, 29478780, 29520813, 30128536, 31050813, 30613976, 30851065, 30426508, 24595525, 30322717, 31159747, 31784482, 30303537, 31447099, 32832836, 31263571, 31948886, 34426522, 32885271, 33193653, 32830346, 32906215, 36139606, 35441217, 35245693, 35418818, 35264596, 33471991, 22114986, 36136322, 22419737, 37449874, 19782031, 36495689, 33850299, 36368126, 36243179, 34326862, 37628581, 38075165)
Comment:
CHEK2: PM1, PS3:Moderate, BP4
Comment:
This variant is considered likely benign based on an internal history weighting algorithm that has been validated and shown to have greater than 99.5% positive and negative predictive values [PMID: 25085752]. The algorithm shows this variant is not strongly associated with more severe personal and family histories of cancer which would be expected if this variant were disease causing. Curve available upon request.
Comment:
The CHEK2 p.Thr476Met variant was identified in 5 of 3910 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and non-BRCA hereditary breast cancer cases of Bulgarian and French ethnicity, and was not identified in 3244 control chromosomes from healthy individuals (Angelova 2012, Desrichard 2011, Le Calvez-Kelm 2011). However among these studies, the frequencies were not consistent and ranged from 0.01 to 0.0004. An additional large study identified the variant in 67 of 91758 proband chromsomes (freq. 0.0007) from individuals who underwent panel testing that including CHEK2 (Leedom 2016 27751358). The variant was also identified in dbSNP (ID: rs142763740) as “with likely pathogenic allele”, in ClinVar and Clinvitae databases (as likely pathogenic by GeneDx, Ambry Genetics, Illumina clinical Services, Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C, Quest Diagnostics Nichols Institute San Juan Capistrano as uncertain significance by Invitae, University of Washington Department of Laboratory Medicine and Genetic Services Laboratory, University of Chicago). The variant is further listed in the Zhejiang University database with no classification. The variant was not identified in Cosmic and MutDB databases. The same amino acid change but different nucleotide change (c.1427C>A) was observed in a patient with a clinical diagnosis of Li-Fraumeni syndrome (Sardi 2014). The variant is identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and the NHLBI GO Exome Sequencing Project in 3 of 4698 European American alleles. In addition, the variant was identified in control databases in 84 of 260146 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 6 of 22580 chromosomes (freq: 0.0003), “other” in 7 of 6276 chromosomes (freq: 0.001), Latino in 6 of 34216 chromosomes (freq: 0.0002), European Non-Finnish in 65 of 122014 chromosomes (freq: 0.0005); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. In order to evaluate mutations in all parts of the CHEK2 gene with a single biological test, an assay to evaluate CHEK2-mediated response to DNA damage was developed based on complementation of S. cerevisiae rad53 by human CHEK2. Based on growth of the strain after DNA damage, the p.Thr476Met variant was found to be damaging (Roeb 2012). The p.Thr476Met variant, which maps to the kinase domain of CHEK2, is likely to disrupt the protein function (Angelova 2012). In one study, the p.Thr476Met variant did not display kinase activity consistently and was classified as probably deleterious (Desrichard 2011). However additional functional studies are needed to determine that the p.Thr476Met variant disrupts the biological function of CHEK2. The p.Thr476 residue is conserved in in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Thr476Met variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Comment:
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative
Comment:
Colon Carcinoma
Comment:
The CHEK2 c.1427C>T variant is predicted to result in the amino acid substitution p.Thr476Met. This variant has been reported in multiple individuals with breast cancer, with a recent study reporting an odds ratio of 1.35 (95% CI=1.03-1.77, P-value=0.03) (Table S1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Desrichard et al. 2011. PubMed ID: 22114986; Roeb et al. 2012. PubMed ID: 22419737; Angelova et al. 2012. PubMed ID: 22862163; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Schubert et al. 2019. PubMed ID: 30426508; Lerner-Ellis et al. 2020. PubMed ID: 31784482; Figure 2, Bychkovsky et al. 2022. PubMed ID: 36136322). This variant has also been reported in individuals with ovarian cancer, prostate cancer, pancreatic cancer, and colorectal cancer (Table S1, Hu et al. 2016. PubMed ID: 26483394; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table 1, Isaacsson Velho et al. 2018. PubMed ID: 29368341; Table 1, Young et al. 2018. PubMed ID: 29945567; Table S4, Bertelsen et al. 2019. PubMed ID: 31263571; Table S3, Arvai et al. 2019. PubMed ID: 31341520). In vitro and in vivo experimental studies suggest this variant results in reduced or absent kinase activity and DNA damage response (Desrichard et al. 2011. PubMed ID: 22114986; Table 1, Roeb et al. 2012. PubMed ID: 22419737; Figure 1, Kleiblova et al. 2019. PubMed ID: 31050813). An additional functional study using protein expression in yeast found that his variant results in semi-functional kinase activity (Delimitsou et al. 2019. PubMed ID: 30851065). In the gnomAD public population database this variant has been reported in up to ~0.05% of alleles in a subpopulation and has conflicting interpretations of uncertain, risk allele, and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128060/). Taken together, we interpret c.1427C>T (p.Thr476Met) as likely pathogenic.
Comment:
Variant interpreted as Uncertain significance and reported on 11-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Across three studies, the c.1427C>T (p.Thr476Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild-type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as likely pathogenic for breast cancer.
Comment:
The CHEK2 c.1427C>T (p.Thr476Met) missense variant, also referred to as c.1556C>T (p.Thr519Met), was reported in five of 1,955 breast cancer patients (Le Calvez-Kelm et al. 2011; Desrichard et al. 2011; Angelova et al. 2012). The variant was absent from a total of 1,622 controls, but is reported at a frequency of 0.00068 in the European (non-Finnish) population of the Exome Aggregation Consortium. Desrichard et al. (2011) developed an in vitro kinase activity assay to assess the activity of missense variants in CHEK2. In this assay the p.Thr476Met variant demonstrated no kinase activity and was similar to a known non-functional kinase variant of CHEK2. In addition, Roeb et al. (2012) developed a yeast-based in-vivo functional assay to assess the effect of CHEK2 variants on the repair of DNA damage. Cells with wild type CHEK2 repaired the DNA damage while cells with a known non-functional variant of CHEK2 did not. The p.Thr476Met variant was shown to have loss of function by this DNA damage response assay. Based on the evidence, the p.Thr476Met variant is classified as pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
PS3, PM2, PM5
Comment:
The p.T476M variant (also known as c.1427C>T), located in coding exon 12 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1427. The threonine at codon 476 is replaced by methionine, an amino acid with similar properties. Recent case-control studies have reported association with breast cancer risk with odds ratios ranging from 1.35 to 1.63 (Dorling et al. N Engl J Med. 2021 02;384:428-439; Bychkovsky BL et al. JAMA Oncol. 2022 Sep). Functional studies of this alteration have reported conflicting findings. In one in vivo, yeast-based growth rate assay, this variant was indicated to be semi-functional (Delimitsou A. Hum Mutat. 2019 05;40(5):631-648). However, several other studies have reported the variant as deleterious based on kinase and DNA damage response activity (Desrichard A et al. Breast Cancer Res. 2011 Nov;13:R119; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). Another study reported this alteration as deleterious in an in vitro assay of kinase activity using bacterially expressed CHEK2, but neutral in an assay conducted in a human cell line (Kleiblova P et al Int J Cancer. 2019 10;145(7):1782-1797). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is interpreted as a moderate risk mutation, also referred to as an established risk allele.
Comment:
Variant summary: CHEK2 c.1427C>T (p.Thr476Met) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 238040 control chromosomes. The observed variant frequency is approximately the same as the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is benign. Additionally, this variant has been observed in 8 individuals who are reportedly cancer free at age 70 in the FLOSSIES database. In addition, co-occurrences with other pathogenic variants have been observed at our laboratory (BRCA2 c.8677C>T, p.Gln2893*; PMS2 c.2444C>T, p.Ser815Leu), providing additional supporting evidence for a benign role. c.1427C>T has been reported in the literature in individuals affected with a variety of cancers such as Breast, Ovarian, Colorectal, and Pancreatic cancers (example, Le Calvez-Kelm_2011, Angelova_2012, Susswein_2015, Hu_2016, Schuber_2019, Henn_2019, Bertelsen_2019, Lerner-Ellis_2019). For some of these cases multigenic panel screening was performed, however, in most cases, the co-occurrence information was not provided and segregation studies were not performed. In addition, Leedom_2016 reported similar frequencies for the variant in their affected (at risk) population of European descent (0.07%; 46/62392 chromosomes tested). This variant was identified in an individual who tested positive for a large deletion encompassing exon 9-15 of CHEK2 in trans in an internal specimen.These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in disruption of CHEK2 kinase activity in vitro and impairs DNA damage response in a yeast assay (example, Desrichard_2011; Roeb_2012, Delimitsou_2019), suggesting a deleterious outcome or at least a possible modifying role of the variant in carcinogenesis. The following publications have been ascertained in the context of this evaluation (PMID: 22862163, 31341520, 31398194, 27621404, 31263571, 35643632, 28944238, 30851065, 22114986, 15095295, 28495237, 30680046, 26483394, 29922827, 29368341, 21244692, 27751358, 31784482, 30128536, 28008555, 27443514, 22419737, 30426508, 26845104, 26681312, 26787654, 29945567, 28135145, Young_2016). ClinVar contains an entry for this variant (Variation ID: 128060). Based on the evidence outlined above, the variant was classified as uncertain significance.
Comment:
This variation detected results in the substitution of the amino acid Threonine with Methionine at codon 476 of the CHEK2 protein. The threonine residue is highly conserved among species in the Protein kinase domain of the protein and there is physiochemical difference between threonine and methionine (Grantham Score 81). This variant has been described in the international literature in individuals affected with breast and endometrial cancers (PMID: 21244692, PMID: 27443514).This variant is present in mutation databases at a low frequency (rs142763740, ExAC 0.07%). The mutation database ClinVar contains entries for this variant (Variation ID: 128060). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein, a prediction supported also by experimental studies. (PMID: 22114986, PMID: 22419737).
Comment:
DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.1427C>T, in exon 13 that results in an amino acid change, p.Thr476Met. This sequence change has been described in the gnomAD population databases with a global population frequency of 0.03% (dbSNP rs142763740); however, this variant is present in a homologous region of the CHEK2 gene and therefore population data for this region may not be reliable. The p.Thr476Met change affects a highly conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. The p.Thr476Met substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Thr476Met change has been identified in patients with a personal and/or family history of breast cancer colorectal cancer, prostate cancer, and pancreatic cancer (PMIDs: 21244692, 27443514, 28944238, 29368341, 29520813, 28008555). Additionally, a different sequence change affecting the same amino acid residue (p.Thr476Lys) has been reported in an individual affected with prostate cancer (PMID: 16835864).. Experimental studies have shown that this missense change disrupts CHEK2 kinase activity in vitro and impairs DNA damage response (PMID: 22114986, 22419737).
Comment:
reported as secondary finding
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 476 of the CHEK2 protein (p.Thr476Met). This variant is present in population databases (rs142763740, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, and/or prostate cancer (PMID: 21244692, 27443514, 28008555, 28944238, 29368341, 29520813, 31050813). ClinVar contains an entry for this variant (Variation ID: 128060). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a low probability of being pathogenic (external communication). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 22114986, 22419737, 30851065, 31050813). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Criteria applied: PS4_MOD,PP3
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 476 of the CHEK2 protein (p.Thr476Met). This variant is present in population databases (rs142763740, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, and/or prostate cancer (PMID: 21244692, 27443514, 28008555, 28944238, 29368341, 29520813, 31050813). ClinVar contains an entry for this variant (Variation ID: 128060). In addition, the in silico prediction for this alteration is inconclusive. . Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 22114986, 22419737, 30851065, 31050813). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The CHEK2 c.1427C>T; p.Thr476Met variant (rs142763740) is reported in numerous individuals with CHEK2-associated cancers (Classen 2013, Girard 2019, Hu 2018, Kamihara 2022, Le Calvez-Kelm 2011, Lilyquist 2017, Rizzolo 2019, Sutcliffe 2020), but is also reported in individuals without cancer suggesting reduced penetrance (Girard 2019). The overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). In vitro kinase assays and in vivo DNA damage response assays with the variant protein showed a loss of kinase activity and impaired function (Delimitsou 2019, Desrichard 2011, Kleiblova 2019, Roeb 2012). However, one CHEK2-cell based assay showed no effect of the variant on protein function (Kleiblova 2019). This variant is reported by multiple laboratories in ClinVar (Variation ID: 128060). It is found in the general population with an overall allele frequency of 0.03% (83/265178 alleles) in the Genome Aggregation Database. The threonine at codon 476 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.445). Based on the currently available information, this variant is considered to be likely pathogenic. References: Classen CF et al. Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis. Hum Genet. 2013 Jul;132(7):825-41. PMID: 23552953. Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. PMID: 30851065. Desrichard A et al. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res. 2011;13(6):R119. PMID: 22114986. Girard E et al. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. Int J Cancer. 2019 Apr 15;144(8):1962-1974. PMID: 30303537. Hu C et al. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. 2018 Jun 19;319(23):2401-2409. PMID: 29922827. Kamihara J et al. Germline pathogenic variants in cancer risk genes among patients with thyroid cancer and suspected predisposition. Cancer Med. 2022 Apr;11(8):1745-1752. PMID: 35174967. Kleiblova P et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797. PMID: 31050813. Le Calvez-Kelm F et al. Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 2011 Jan 18;13(1):R6. PMID: 21244692. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Rizzolo P et al. Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. Int J Cancer. 2019 Jul 15;145(2):390-400. PMID: 30613976. Roeb W et al. Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Hum Mol Genet. 2012 Jun 15;21(12):2738-44. PMID: 22419737. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. PMID: 26484312. Sutcliffe EG et al. Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing. Cancer Genet. 2020 Aug;246-247:12-17. PMID: 32805687.
Comment:
In the published literature, this variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMIDs: 32658311 (2021), 33030641 (2020), 32906215 (2020), 31050813 (2019), 30287823 (2018), 28008555 (2017), 22862163 (2012), 21244692 (2011)), endometrial cancer (PMID: 27443514 (2016)), pancreatic cancer (PMID: 26845104 (2016)), colorectal cancer (PMIDs: 32658311 (2021), 28944238 (2017)), and prostate cancer (PMIDs: 32832836 (2020), 29520813 (2018)). This variant has also been reported in unaffected individuals (PMIDs: 32658311 (2021), 31050813 (2019), 30287823 (2018)). Additionally, experimental studies have reported conflicting results in this variant's impact on CHEK2 protein functions (PMIDs: 31050813 (2019), 30851065 (2019), 22419737 (2012)), 22114986 (2011)). The frequency of this variant in the general population, 0.0005 (62/124190 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces threonine with methionine at codon 476 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have demonstrated inconsistent results. The mutant protein has shown significantly reduced kinase activity in vitro using bacteria produced protein (PMID: 22114986, 31050813), but displayed normal kinase activity in a human cell assay (PMID: 31050813, 37449874). DNA damage repair assays in yeast have shown the mutant protein to exhibit partial to complete loss of function (PMID: 22419737, 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 15095295, 21244692, 22114986, 22862163, 24595525, 25186627, 26681312, 28008555, 28495237 30426508, 32658311, 32805687, 32906215, 33030641, 36315097, 37628581), prostate cancer (PMID: 29368341, 29520813), colorectal cancer (PMID: 28008555, 28135145, 28944238, 32658311), pancreatic cancer (PMID: 26483394, 26845104 29945567), and endometrial cancer (PMID: 27443514), as well as in individuals unaffected with cancer (PMID: 32658311). A history weighting algorithm score was inconsistent with that expected for CHEK2 pathogenic mutations (Mundt, et al. poster #154, ACMG 2017). This variant has been identified in 83/265178 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has been reported in two large case-control meta analyses; this variant has been identified in 83/60383 cases and 45/53416 controls (OR=1.632, 95%CI [1.135 to 2.346]) (PMID: 33471991) and 101/73048 BC cases and 60/88658 controls (OR=2.043, 95%Ci [1.4841 to 2.8125]) (PMID: 37449874). In summary, functional studies have been inconclusive regarding the impact of this variant on protein function, and this variant has been observed in individuals affected with breast cancer as well as in the general population. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Case control studies suggest this variant is associated with breast cancer, although odds ratios are only modestly elevated (around 1.5 or less) (PMID: 33471991, 36136322, 37449874); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26681312, 29368341, 21244692, 29945567, 28944238, 25186627, 26845104, 22862163, 23552953, 28008555, no PMID, 10617473, 32782288, 34028844, 32805687, 32522261, 34637943, 35220195, 32923877, 29922827, 35174967, 28888541, 26787654, 26483394, 27751358, 21901162, 28495237, 27621404, 26022348, 27443514, 15095295, 29478780, 29520813, 30128536, 31050813, 30613976, 30851065, 30426508, 24595525, 30322717, 31159747, 31784482, 30303537, 31447099, 32832836, 31263571, 31948886, 34426522, 32885271, 33193653, 32830346, 32906215, 36139606, 35441217, 35245693, 35418818, 35264596, 33471991, 22114986, 36136322, 22419737, 37449874, 19782031, 36495689, 33850299, 36368126, 36243179, 34326862, 37628581, 38075165)
Comment:
CHEK2: PM1, PS3:Moderate, BP4
Comment:
This variant is considered likely benign based on an internal history weighting algorithm that has been validated and shown to have greater than 99.5% positive and negative predictive values [PMID: 25085752]. The algorithm shows this variant is not strongly associated with more severe personal and family histories of cancer which would be expected if this variant were disease causing. Curve available upon request.
Comment:
The CHEK2 p.Thr476Met variant was identified in 5 of 3910 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and non-BRCA hereditary breast cancer cases of Bulgarian and French ethnicity, and was not identified in 3244 control chromosomes from healthy individuals (Angelova 2012, Desrichard 2011, Le Calvez-Kelm 2011). However among these studies, the frequencies were not consistent and ranged from 0.01 to 0.0004. An additional large study identified the variant in 67 of 91758 proband chromsomes (freq. 0.0007) from individuals who underwent panel testing that including CHEK2 (Leedom 2016 27751358). The variant was also identified in dbSNP (ID: rs142763740) as “with likely pathogenic allele”, in ClinVar and Clinvitae databases (as likely pathogenic by GeneDx, Ambry Genetics, Illumina clinical Services, Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C, Quest Diagnostics Nichols Institute San Juan Capistrano as uncertain significance by Invitae, University of Washington Department of Laboratory Medicine and Genetic Services Laboratory, University of Chicago). The variant is further listed in the Zhejiang University database with no classification. The variant was not identified in Cosmic and MutDB databases. The same amino acid change but different nucleotide change (c.1427C>A) was observed in a patient with a clinical diagnosis of Li-Fraumeni syndrome (Sardi 2014). The variant is identified in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and the NHLBI GO Exome Sequencing Project in 3 of 4698 European American alleles. In addition, the variant was identified in control databases in 84 of 260146 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 6 of 22580 chromosomes (freq: 0.0003), “other” in 7 of 6276 chromosomes (freq: 0.001), Latino in 6 of 34216 chromosomes (freq: 0.0002), European Non-Finnish in 65 of 122014 chromosomes (freq: 0.0005); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. In order to evaluate mutations in all parts of the CHEK2 gene with a single biological test, an assay to evaluate CHEK2-mediated response to DNA damage was developed based on complementation of S. cerevisiae rad53 by human CHEK2. Based on growth of the strain after DNA damage, the p.Thr476Met variant was found to be damaging (Roeb 2012). The p.Thr476Met variant, which maps to the kinase domain of CHEK2, is likely to disrupt the protein function (Angelova 2012). In one study, the p.Thr476Met variant did not display kinase activity consistently and was classified as probably deleterious (Desrichard 2011). However additional functional studies are needed to determine that the p.Thr476Met variant disrupts the biological function of CHEK2. The p.Thr476 residue is conserved in in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Thr476Met variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Comment:
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative
Comment:
Colon Carcinoma
Comment:
The CHEK2 c.1427C>T variant is predicted to result in the amino acid substitution p.Thr476Met. This variant has been reported in multiple individuals with breast cancer, with a recent study reporting an odds ratio of 1.35 (95% CI=1.03-1.77, P-value=0.03) (Table S1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Desrichard et al. 2011. PubMed ID: 22114986; Roeb et al. 2012. PubMed ID: 22419737; Angelova et al. 2012. PubMed ID: 22862163; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Schubert et al. 2019. PubMed ID: 30426508; Lerner-Ellis et al. 2020. PubMed ID: 31784482; Figure 2, Bychkovsky et al. 2022. PubMed ID: 36136322). This variant has also been reported in individuals with ovarian cancer, prostate cancer, pancreatic cancer, and colorectal cancer (Table S1, Hu et al. 2016. PubMed ID: 26483394; Table S1, Susswein et al. 2016. PubMed ID: 26681312; Table 1, Isaacsson Velho et al. 2018. PubMed ID: 29368341; Table 1, Young et al. 2018. PubMed ID: 29945567; Table S4, Bertelsen et al. 2019. PubMed ID: 31263571; Table S3, Arvai et al. 2019. PubMed ID: 31341520). In vitro and in vivo experimental studies suggest this variant results in reduced or absent kinase activity and DNA damage response (Desrichard et al. 2011. PubMed ID: 22114986; Table 1, Roeb et al. 2012. PubMed ID: 22419737; Figure 1, Kleiblova et al. 2019. PubMed ID: 31050813). An additional functional study using protein expression in yeast found that his variant results in semi-functional kinase activity (Delimitsou et al. 2019. PubMed ID: 30851065). In the gnomAD public population database this variant has been reported in up to ~0.05% of alleles in a subpopulation and has conflicting interpretations of uncertain, risk allele, and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128060/). Taken together, we interpret c.1427C>T (p.Thr476Met) as likely pathogenic.
Comment:
Variant interpreted as Uncertain significance and reported on 11-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Impact of High-to-Moderate Penetrance Genes on Genetic Testing: Looking over Breast Cancer. | Turchiano A | Genes | 2023 | PMID: 37628581 |
| ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk. | Stolarova L | Clinical cancer research : an official journal of the American Association for Cancer Research | 2023 | PMID: 37449874 |
| Somatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants. | Lim BWX | Journal of the National Cancer Institute | 2023 | PMID: 36315097 |
| Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care-Checking CHEK2. | Bychkovsky BL | JAMA oncology | 2022 | PMID: 36136322 |
| CHEK2 variants: linking functional impact to cancer risk. | Boonen RACM | Trends in cancer | 2022 | PMID: 35643632 |
| Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance. | Castillo-Guardiola V | European journal of medical genetics | 2022 | PMID: 35245693 |
| Germline variant testing in serrated polyposis syndrome. | Murphy A | Journal of gastroenterology and hepatology | 2022 | PMID: 35128723 |
| Concurrent pathogenic variations in patients with hereditary cancer syndromes. | Agaoglu NB | European journal of medical genetics | 2021 | PMID: 34637943 |
| Investigation of Hereditary Cancer Predisposition Genes of Patients with Colorectal Cancer: Single-centre Experience. | Duzkale N | Journal of the College of Physicians and Surgeons--Pakistan : JCPSP | 2021 | PMID: 34271781 |
| Study of the Genetic Variants in BRCA1/2 and Non-BRCA Genes in a Population-Based Cohort of 2155 Breast/Ovary Cancer Patients, Including 443 Triple-Negative Breast Cancer Patients, in Argentina. | Solano AR | Cancers | 2021 | PMID: 34072659 |
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Bilateral Disease Common Among Slovenian CHEK2-Positive Breast Cancer Patients. | Nizic-Kos T | Annals of surgical oncology | 2021 | PMID: 33030641 |
| Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
| Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity. | Smith PS | Genes, chromosomes & cancer | 2021 | PMID: 32830346 |
| Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. | Akcay IM | International journal of cancer | 2021 | PMID: 32658311 |
| New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients. | Djursby M | Frontiers in genetics | 2020 | PMID: 33193653 |
| Comprehensive analysis and ACMG-based classification of CHEK2 variants in hereditary cancer patients. | Vargas-Parra G | Human mutation | 2020 | PMID: 32906215 |
| Paired tumor sequencing and germline testing in breast cancer management: An experience of a single academic center. | Elliott E | Cancer reports (Hoboken, N.J.) | 2020 | PMID: 32881420 |
| Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing. | Sutcliffe EG | Cancer genetics | 2020 | PMID: 32805687 |
| Ancestry-specific hereditary cancer panel yields: Moving toward more personalized risk assessment. | Roberts ME | Journal of genetic counseling | 2020 | PMID: 32227564 |
| Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer. | Wu Y | European urology oncology | 2020 | PMID: 31948886 |
| Retesting of women who are negative for a BRCA1 and BRCA2 mutation using a 20-gene panel. | Lerner-Ellis J | Journal of medical genetics | 2020 | PMID: 31784482 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: [email protected] | American journal of human genetics | 2019 | PMID: 31447099 |
| Computational analysis of high-risk SNPs in human CHK2 gene responsible for hereditary breast cancer: A functional and structural impact. | Badgujar NV | PloS one | 2019 | PMID: 31398194 |
| Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls. | Arvai KJ | Hereditary cancer in clinical practice | 2019 | PMID: 31341520 |
| High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer. | Bertelsen B | NPJ genomic medicine | 2019 | PMID: 31263571 |
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
| Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. | Kleiblova P | International journal of cancer | 2019 | PMID: 31050813 |
| Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
| Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes. | Henn J | Hereditary cancer in clinical practice | 2019 | PMID: 30680046 |
| Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. | Rizzolo P | International journal of cancer | 2019 | PMID: 30613976 |
| The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants. | Schubert S | International journal of cancer | 2019 | PMID: 30426508 |
| Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
| Absence of EIF1AX, PPM1D, and CHEK2 mutations reported in Thyroid Cancer Genome Atlas (TCGA) in a large series of thyroid cancer. | Alzahrani AS | Endocrine | 2019 | PMID: 30269267 |
| Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing. | Lu HM | JAMA oncology | 2019 | PMID: 30128536 |
| Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
| Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
| Pancreatic cancer as a sentinel for hereditary cancer predisposition. | Young EL | BMC cancer | 2018 | PMID: 29945567 |
| Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. | Hu C | JAMA | 2018 | PMID: 29922827 |
| A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. | Wu Y | The Prostate | 2018 | PMID: 29520813 |
| Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. | Isaacsson Velho P | The Prostate | 2018 | PMID: 29368341 |
| Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. | DeRycke MS | Molecular genetics & genomic medicine | 2017 | PMID: 28944238 |
| Multigene panels in Ashkenazi Jewish patients yield high rates of actionable mutations in multiple non-BRCA cancer-associated genes. | Frey MK | Gynecologic oncology | 2017 | PMID: 28495237 |
| Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
| Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. | Pritzlaff M | Breast cancer research and treatment | 2017 | PMID: 28008555 |
| The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families? | Eliade M | Oncotarget | 2017 | PMID: 27779110 |
| Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers. | Leedom TP | Cancer genetics | 2016 | PMID: 27751358 |
| Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing. | Balmaña J | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 27621404 |
| Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. | Ring KL | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2016 | PMID: 27443514 |
| Improving performance of multigene panels for genomic analysis of cancer predisposition. | Shirts BH | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26845104 |
| Multigene testing of moderate-risk genes: be mindful of the missense. | Young EL | Journal of medical genetics | 2016 | PMID: 26787654 |
| Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
| Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. | Hu C | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2016 | PMID: 26483394 |
| Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
| Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
| Retroperitoneal dedifferentiated liposarcoma lacking MDM2 amplification in a patient with a germ line CHEK2 mutation. | Sadri N | Virchows Archiv : an international journal of pathology | 2014 | PMID: 24595525 |
| Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis. | Classen CF | Human genetics | 2013 | PMID: 23552953 |
| CHEK2 gene alterations independently increase the risk of death from breast cancer in Bulgarian patients. | Angelova SG | Neoplasma | 2012 | PMID: 22862163 |
| Response to DNA damage of CHEK2 missense mutations in familial breast cancer. | Roeb W | Human molecular genetics | 2012 | PMID: 22419737 |
| CHEK2 contribution to hereditary breast cancer in non-BRCA families. | Desrichard A | Breast cancer research : BCR | 2011 | PMID: 22114986 |
| Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. | Le Calvez-Kelm F | Breast cancer research : BCR | 2011 | PMID: 21244692 |
| Limited relevance of the CHEK2 gene in hereditary breast cancer. | Dufault MR | International journal of cancer | 2004 | PMID: 15095295 |
| click to load more click to collapse | ||||
Text-mined citations for rs142763740 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.