This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.190G>A (p.Glu64Lys)
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.
(37)
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
Likely pathogenic(11); Uncertain significance(18)
Likely pathogenic(11); Uncertain significance(18)
37
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.190G>A (p.Glu64Lys)
Variation ID: 128068 Accession: VCV000128068.99
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q12.1 22: 28734532 (GRCh38) [ NCBI UCSC ] 22: 29130520 (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 Jan 31, 2016 Nov 24, 2024 Sep 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007194.4:c.190G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Glu64Lys missense NM_001005735.2:c.190G>A NP_001005735.1:p.Glu64Lys missense NM_001257387.2:c.-588G>A 5 prime UTR NM_001349956.2:c.190G>A NP_001336885.1:p.Glu64Lys missense NM_145862.2:c.190G>A NP_665861.1:p.Glu64Lys missense NC_000022.11:g.28734532C>T NC_000022.10:g.29130520C>T NG_008150.2:g.12335G>A LRG_302:g.12335G>A LRG_302t1:c.190G>A LRG_302p1:p.Glu64Lys O96017:p.Glu64Lys - Protein change
- E64K
- Other names
-
p.E64K:GAG>AAG
- Canonical SPDI
- NC_000022.11:28734531:C:T
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00015
Exome Aggregation Consortium (ExAC) 0.00016
The Genome Aggregation Database (gnomAD), exomes 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00016
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
- 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 31, 2024 | RCV000116009.35 | |
| Conflicting interpretations of pathogenicity (9) |
criteria provided, conflicting classifications
|
Aug 26, 2024 | RCV000212407.58 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 9, 2019 | RCV000210191.13 | |
| Conflicting interpretations of pathogenicity (8) |
criteria provided, conflicting classifications
|
Mar 27, 2024 | RCV000199067.37 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001356247.10 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Jul 30, 2021 | RCV001270935.11 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 31, 2024 | RCV002465520.11 | |
|
Predisposition to cancer
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 3, 2022 | RCV003153376.8 |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
May 3, 2024 | RCV002265610.9 | |
|
CHEK2-related disorder
|
Likely pathogenic (1) |
no assertion criteria provided
|
Aug 21, 2024 | RCV004528806.2 |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Sep 11, 2024 | RCV003338414.3 | |
| Uncertain significance (2) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV004556726.1 | |
| 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
(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: SCV001310491.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
|
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Likely pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917231.4
First in ClinVar: Jun 02, 2019 Last updated: Aug 26, 2023 |
Comment:
Variant summary: CHEK2 c.190G>A (p.Glu64Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: CHEK2 c.190G>A (p.Glu64Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251468 control chromosomes, predominantly at a frequency of 0.0003 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency of a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (0.00031), suggesting that it could be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, a high-homology CHEK2 pseudogene may confound these results and interpretation must be performed cautiously, allowing no conclusion about variant significance.c.190G>A has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (examples: Desrichard_2011, Susswein_2015, Kraus_2016, Shirts_2016, Carter_2018, Girard_2019, Kleiblova_2019, Tsaousis_2019, Hou_2020, Heygate_2020, Toss_2020, Rodriguez-Balada_2020, Vargas-Parra_2020, and Dorling 2021) without evidence for causality, but also in controls (examples: Girard_2019, Kleiblova_2019, and Dorling 2021). However, in at least one family study, 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals were reported, thus the variant did not co-segregate with disease (Kleiblova_2019). In addition, a recent case-control analysis showed that this variant is associated with breast cancer (Boonen_2022). The variant has also been reported in individuals with other cancer phenotypes, including colorectal cancer (examples- Susswein_2015, Rohlin_2016, Yurgelun_2017), prostate cancer (examples-Dong_2003, Wu_2006, Pritchard_2016, Abida_2017), and hereditary pancreatic cancer (example- Chaffee_2018). Several publications report experimental evidence evaluating an impact on protein function. Assays performed in yeast model systems have reported conflicting results: one study found that the variant impaired growth following DNA damage (Roeb_2012), while a similar study reported no significant impact on growth (Delimitsou_2019). Other laboratories have reported a reduction in CHEK2-specific phosphorylation and kinase activities in vitro (examples- Wu_2006, Kleiblova_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22419737, 12533788, 26681312, 16835864, 26845104, 22114986, 27621404, 27616075, 27433846, 27696107, 28135145, 28726808, 30851065, 30374176, 30447919, 30322717, 30303537, 31159747, 31398194, 31050813, 28825054, 31786208, 31980526, 32906215, 33471991, 32923877, 33919281, 34903604). Twenty-three ClinVar submitters have assessed the variant since 2014: fourteen classified the variant as uncertain significance and 9 as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Uncertain significance
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185901.10
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.E64K variant (also known as c.190G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide … (more)
The p.E64K variant (also known as c.190G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 190. The glutamic acid at codon 64 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in multiple cohorts of breast, ovarian and prostate cancer patients (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Desrichard A et al. Breast Cancer Res. 2011;13:R119; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Tsai GJ et al. Genet. Med. 2019 06;21:1435-1442; Girard E et al. Int. J. Cancer. 2019 04;144:1962-1974). Functional studies conducted in multiple model systems have conflicting results as to the effect this protein has on substrate phosphorylation and DNA damage response (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Delimitsou A et al. Hum. Mutat. 2019 05;40:631-648; Kleiblova P et al. Int. J. Cancer. 2019 10;145:1782-1797; Boonen RACM et al. Cancer Res. 2022 Feb;82(4):615-631; Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). Although this variant may segregate incompletely with disease, co-segregation analysis should be used with extreme caution for genes with low relative risk like CHEK2 (Belman S et al. Genet. Med. 2020 Dec;22:2052-2059). This amino acid position is poorly conserved in available vertebrate species. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
|
|
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Uncertain significance
(Mar 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005057504.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
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Uncertain significance
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821997.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
|
|
|
Likely pathogenic
(Sep 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and colorectal cancer, susceptibility to
(Autosomal dominant inheritance)
Affected status: yes, unknown
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266168.2
First in ClinVar: Mar 20, 2016 Last updated: Nov 21, 2020 |
Comment:
This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was … (more)
This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was also shown to impact CHEK2 protein function (PMID 22419737). This variant occurs at a position that is moderately evolutionarily conserved and is predicted to be probably damaging by computer analysis with PolyPhen2 and SIFT. This analysis was performed in conjunction with the family studies as part of the University of Washington Find My Variant study. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
breast cancer (present)
Age: 30-39 years
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
breast cancer (present)
Age: 40-49 years
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
pancreatic cancer (present)
Age: 50-59 years
|
|
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Uncertain significance
(Dec 19, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537408.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.190G>A (p.E64K) variant has been reported in heterozygosity in numerous individuals with breast, ovarian, prostate or colorectal cancer (PMID: 12533788, 22114986, 30322717, 30303537, … (more)
The CHEK2 c.190G>A (p.E64K) variant has been reported in heterozygosity in numerous individuals with breast, ovarian, prostate or colorectal cancer (PMID: 12533788, 22114986, 30322717, 30303537, 31050813). In a breast cancer case-control analysis, the variant was seen to be enriched in cases compared to controls: 66/60,466 cases versus 33/53,461 controls (PMID: 33471991). Functional studies have shown that this variant is deleterious to function at cell based, kinase assays (PMID: 31050813, 16835864), but shows inconclusive results in yeast based DNA damage repair assays (PMID 22419737, 30851065). This variant was observed in 38/126668 chromosomes in the European (non-Finnish) population, with no homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID: 128068). In silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
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Uncertain significance
(Jul 30, 2021)
|
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: SCV003838797.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
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Likely pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Predisposition to cancer
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003843063.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
The CHEK2 c.190G>A (p.Glu64Lys) missense change has a maximum subpopulation frequency of 0.030% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant has been widely reported to be … (more)
The CHEK2 c.190G>A (p.Glu64Lys) missense change has a maximum subpopulation frequency of 0.030% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant has been widely reported to be associated with cancer susceptibility (PMID: 12533788, 16835864, 16941491, 22114986, 24082139, 25503501, 26681312, 26845104, 26976419, 27433846, 27616075, 27696107, 27779110, 28135145, 31050813, 31220302). In a large breast cancer case-control analysis, the variant was enriched in breast cancer cases compared to controls (PMID: 33471991). It has also been reported in 11x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (http://whi.color.com). Large co-segregation studies have not been performed, however co-segregation in families is variable and the p.E64K has been observed in at least one individual who also harbored the p.I157T (PMID: 30374176, 31050813). Functional assays have reported that this variant results in reduced phosphorylation and partial disruption of CHEK2 kinase activity (PMID: 16835864, 31050813), however yeast-based DNA damage repair assays are inconclusive about a pathogenic or benign effect (PMID: 22419737, 30851065). In summary, this variant meets criteria to be classified as likely pathogenic with evidence suggesting lower penetrance. (less)
|
|
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Uncertain significance
(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: SCV002009504.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004046969.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant c.190G>A (p.Glu64Lys) in CHEK2 gene has been reported in individuals with breast, ovarian, or prostate cancer (Dong ,et al., 2003) But other … (more)
The missense variant c.190G>A (p.Glu64Lys) in CHEK2 gene has been reported in individuals with breast, ovarian, or prostate cancer (Dong ,et al., 2003) But other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Roeb, et al 2012).This variant has been reported to the ClinVar database as Uncertain Significance.The p.Glu64Lys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0001591 is reported in gnomAD. The amino acid Glu at position 64 is changed to a Lys changing protein sequence and it might alter its composition and physicochemical properties.In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu64Lys in CHEK2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. (less)
Clinical Features:
Neoplasm (present)
|
|
|
Likely pathogenic
(Aug 04, 2023)
|
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: SCV004228059.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
|
|
|
Uncertain significance
(Jun 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004235062.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Likely pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254934.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 64 of the CHEK2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 64 of the CHEK2 protein (p.Glu64Lys). This variant is present in population databases (rs141568342, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a personal and/or family history of breast, prostate, ovarian, colorectal, thyroid, and pancreatic cancer (PMID: 12533788, 22114986, 24082139, 26681312, 26845104, 27616075, 27779110, 28135145; Invitae; External communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128068). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16835864, 22419737). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
|
Likely pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000839503.3
First in ClinVar: Oct 10, 2018 Last updated: Mar 30, 2024 |
|
|
|
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: SCV002761118.4
First in ClinVar: Dec 17, 2022 Last updated: Aug 04, 2024 |
|
|
|
Uncertain significance
(May 03, 2024)
|
criteria provided, single submitter
Method: curation
|
Hereditary breast ovarian cancer syndrome
Affected status: not provided
Allele origin:
germline
|
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV005196405.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
Comment:
Neueste funkt. Daten von Stolarova et al. 2023 neutral in CHK2 assay intermediate in KAP1 Assay. Roeb 2012 kommt hier auf ein ´´damaging´´; Kleiblova 2019 … (more)
Neueste funkt. Daten von Stolarova et al. 2023 neutral in CHK2 assay intermediate in KAP1 Assay. Roeb 2012 kommt hier auf ein ´´damaging´´; Kleiblova 2019 auf ein ´´deleterious´´, Boonen 2021 kommt auf ein ´´intermediate´´ während Delimitosu 2019 die Veränderung als benign einstuft. Boonen et al diskutieren sehr schön die diskordanten Ergebnisse in Hefe und Mensch und zeigen noch ein weiteres Problem der Hefeassays auf, nämlich die Analyse bei 30 Grad statt 37 Grad, was natürlich Auswirkungen auf Proteinstabilitäten hat. Wu X, Dong X, Liu W, et al.: Characterization of CHEK2 mutations in prostate cancer. Hum Mutat 2006;27:742–7 ´´reduced autophosphorylation, CDC25C phosphorylation and severely impaired T68 phosphorylation´´. In der Arbeit von Dorling et al. (BRIDGES/BCAC) wurde die Variante 60X in 60.000 BC cases und 30X in 53.000 Kontrollen gefunden. Vgl. c.1100delC 868X in 60.000 cases und 254X in 53.000 Kontrollen.Evtl. handelt es sich um eine hypomorphe Variante (less)
|
|
|
Likely pathogenic
(Sep 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005368370.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PS3,PS4_MOD
Clinical Features:
Embryonal rhabdomyosarcoma (present)
Sex: female
|
|
|
Likely pathogenic
(Sep 11, 2023)
|
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: SCV001429610.3
First in ClinVar: Aug 15, 2020 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PS3,PS4_MOD
Clinical Features:
Breast neoplasm (present) , Breast carcinoma (present)
Sex: female
|
|
|
Uncertain significance
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005410221.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
BP4
Number of individuals with the variant: 4
|
|
|
Uncertain significance
(Oct 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580504.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3_MOD, PS4_SUP, PP3
|
Number of individuals with the variant: 3
Sex: female
|
|
|
Uncertain significance
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488777.2
First in ClinVar: Jan 31, 2016 Last updated: Dec 24, 2022 |
|
|
|
Uncertain significance
(Mar 28, 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: SCV001474010.4
First in ClinVar: Jan 26, 2021 Last updated: Mar 04, 2023 |
Comment:
The CHEK2 c.190G>A; p.Glu64Lys variant (rs141568342) is reported in the literature in individuals with breast, ovarian, or prostate cancer (Carter 2018, Desrichard 2011, Dong 2003, … (more)
The CHEK2 c.190G>A; p.Glu64Lys variant (rs141568342) is reported in the literature in individuals with breast, ovarian, or prostate cancer (Carter 2018, Desrichard 2011, Dong 2003, Toss 2021). A yeast functional assay suggests this variant is benign (Delimitsou 2019), but other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Kleiblova 2019, Roeb 2012, Wu 2006). This variant is also reported by multiple laboratories in the ClinVar database (Variation ID: 128068) and is found in the general population with an overall allele frequency of 0.02% (45/282814 alleles) in the Genome Aggregation Database. The glutamate at codon 64 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.240). Given the currently available information, the clinical significance of this variant is uncertain at this time. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. 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. Dong X et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003 Feb;72(2):270-80. Epub 2003 Jan 17. PMID: 12533788. 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. 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. Toss A et al. Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers. Genes (Basel). 2021 Apr 21;12(5):616. PMID: 33919281. Wu X et al. Characterization of CHEK2 mutations in prostate cancer. Hum Mutat. 2006 Aug;27(8):742-7. PMID: 16835864. (less)
|
|
|
Likely pathogenic
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004020189.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic … (more)
This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. (less)
|
|
|
Uncertain significance
(Jun 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601160.5
First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with prostate cancer (PMID: 12533788 (2003), 16941491 (2006), 24082139 (2013), 27433846 (2016), 28873162 (2017)), … (more)
In the published literature, this variant has been reported in individuals with prostate cancer (PMID: 12533788 (2003), 16941491 (2006), 24082139 (2013), 27433846 (2016), 28873162 (2017)), breast cancer and or ovarian cancer (PMID: 22419737 (2012), 25186627 (2015), 26976419 (2016), 26681312 (2016), 26845104 (2016), 27616075 (2016), 27779110 (2017), 28779002 (2017), 29555771 (2018), 30322717 (2018), 30303537 (2019), 31050813 (2019), 32923877 (2020), 31786208 (2020), 32805687 (2020), 33919281 (2021), 33471991 (2021)) and colorectal cancer (PMID: 28135145 (2017)). The variant has also been reported in healthy individuals (PMID: 26506619 (2015), 28779002 (2017), 30303537 (2019), 33471991 (2021)). Functional studies have reported conflicting results regarding the effect of this variant on CHEK2 protein function (PMID: 16835864 (2006), 22419737 (2012), 30851065 (2019)). The frequency of this variant in the general population, 0.00031 (16/50798 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Likely pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000902646.5
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with lysine at codon 64 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces glutamic acid with lysine at codon 64 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). Multiple functional studies have shown this variant to disrupt CHEK2 function in kinase assays and DNA damage response (PMID: 16835864, 22419737, 31050813, 33606978, 34903604). One study has shown normal growth of yeast cells expressing the mutant protein following induction of DNA damage (PMID, 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 22114986, 25503501, 26681312, 26845104, 26976419, 27616075, 31050813, 33919281, 36011273, 36315097), colorectal cancer (PMID: 26681312, 27696107, 28135145), ovarian cancer (PMID: 26681312, 27779110), pancreatic cancer (PMID: 26845104), prostate cancer (PMID: 12533788, 16835864, 16941491, 24082139, 27433846, 31220302), and sarcoma (PMID: 35053600). In one study, breast cancer prevalence in women who carry this variant does not show statistically significant difference when compared to women who carry CHEK2 c.1100delC variant (PMID: 32805687). However, this variant has also been reported in two large breast cancer case-control meta-analyses, in 66/60466 cases and 33/53461 unaffected controls; OR=1.769 (95%CI 1.165 to 2.687); (Leiden Open Variation Database DB-ID CHEK2_000075) (PMID: 33471991), and 72/73048 cases and 29/88658 unaffected controls OR=3.0153 (95%CI 1.9592 to 4.6408); (PMID: 37449874). This variant has been identified in 45/282814 chromosomes (39/129148 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). This variant has also been identified in 11 of 9884 females over age 70 without personal history of cancer (FLOSSIES database, https://whi.color.com/variant/22-29130520-C-T). Based on the available evidence, this variant is classified as Likely Pathogenic. Although the penetrance of this variant has not been determined, its elevated frequency in the population and observations in unaffected individuals suggests that this variant may show reduced penetrance. (less)
|
|
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Uncertain significance
(Oct 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197509.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Likely pathogenic
(Aug 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149918.20
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
Observed in individuals with CHEK2-related cancers with case-control comparisons supporting this variant is associated with breast cancer (PMID: 22419737, 34326862, 34903604, 37449874, 37839337); Published functional … (more)
Observed in individuals with CHEK2-related cancers with case-control comparisons supporting this variant is associated with breast cancer (PMID: 22419737, 34326862, 34903604, 37449874, 37839337); Published functional studies demonstrate intermediate to impaired auto-phosphorylation and kinase activity, with some conflicting results (PMID: 16835864, 22419737, 30851065, 31050813, 34903604, 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, 27616075, 28135145, 29522266, 27779110, 27433846, 31786208, 33919281, 35053600, 32906215, 22419737, 16835864, 24082139, 16941491, 22114986, 12533788, 27067391, 26976419, 26506619, 26845104, 27696107, 28135136, 27621404, 28726808, 28873162, 29555771, 29555025, 10973490, 30851065, 31050813, 31220302, 30322717, 31159747, 30303537, 30374176, 31101557, 32805687, 31980526, 32708810, 34426522, 34903604, 33606978, 32522261, 32923877, 35101071, 33047316, 33471991, 38061684, 34326862, 37449874, 36011273, 36315097, 35127508, 37507557, 37839337, 11733767) (less)
|
|
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Uncertain significance
(Jul 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892320.28
First in ClinVar: Mar 31, 2019 Last updated: Oct 20, 2024 |
Comment:
CHEK2: PS4, PS3:Moderate, BS2
Number of individuals with the variant: 3
|
|
|
Likely pathogenic
(Sep 09, 2019)
|
no assertion criteria provided
Method: research
|
CHEK2-Related Cancer Susceptibility
Affected status: yes
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV001446371.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020
Comment:
This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was … (more)
This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was also shown to impact CHEK2 protein function (PMID: 22419737). This variant occurs at a position that is moderately evolutionarily conserved and is predicted to be probably damaging by computer analysis with PolyPhen2 and SIFT. Taken together this variant is considered likely pathogenic. This analysis was performed in conjunction with the family studies as part of the University of Washington Find My Variant study. (less)
|
|
|
|
Likely pathogenic
(Jun 11, 2019)
|
no assertion criteria provided
Method: case-control, clinical testing
|
Breast and/or ovarian cancer
Affected status: yes, no
Allele origin:
germline
|
CZECANCA consortium
Accession: SCV001451739.1
First in ClinVar: Dec 26, 2020 Last updated: Dec 26, 2020 |
Observation 1:
Number of individuals with the variant: 1
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
Observation 2:
Number of individuals with the variant: 2
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
|
|
|
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: SCV001551362.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CHEK2 p.Glu64Lys variant was identified in 16 of 30462 proband chromosomes (frequency: 0.0005) from individuals or families with breast, prostate, and colon cancer and … (more)
The CHEK2 p.Glu64Lys variant was identified in 16 of 30462 proband chromosomes (frequency: 0.0005) from individuals or families with breast, prostate, and colon cancer and was also identified in 1 of 1872 control chromosomes from healthy individuals (Desrichard 2011, Balmana 2016, Mandelker 2017, Susswein 2015, Rohlin 2016, Dong 2003, Wu 2006, Kraus 2017, Shirts 2016, Havranek 2015). The variant was also identified in dbSNP (ID: rs141568342) as "With Likely Pathogenic allele", in ClinVar (classified as likely pathogenic by GeneDx and a variant of uncertain significance by Ambry, Invitae, UWDLP, Counsyl and QDNISJC), and Zhejiang University database (3x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 44 of 277158 chromosomes at a frequency of 0.00016 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24020 chromosomes (freq: 0.00008), Latino in 2 of 34420 chromosomes (freq: 0.00006), European Non-Finnish in 38 of 126668 chromosomes (freq: 0.0003), and South Asian in 2 of 30782 chromosomes (freq: 0.00007). The variant was not observed in the “Other”, Ashkenazi Jewish, East Asian or Finnish populations. Functional analyses suggesting that this variant is pathogenic have shown reduced phosphorylation and kinase activity as well as loss of DNA damage response (Wu 2006, Roeb 2012). The p.Glu64Lys residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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)
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|
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Likely pathogenic
(May 18, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
Cancer Genomics Lab, PINUM Cancer Hospital
Accession: SCV004011747.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
Age: 30-39 years
Sex: female
Ethnicity/Population group: Pakistani
|
|
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Likely pathogenic
(Aug 21, 2024)
|
no assertion criteria provided
Method: clinical testing
|
CHEK2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806876.4
First in ClinVar: Dec 19, 2017 Last updated: Oct 08, 2024 |
Comment:
The CHEK2 c.190G>A variant is predicted to result in the amino acid substitution p.Glu64Lys. This variant has been reported in individuals with a personal or … (more)
The CHEK2 c.190G>A variant is predicted to result in the amino acid substitution p.Glu64Lys. This variant has been reported in individuals with a personal or family history of prostate, breast, ovarian, and colon cancer (Dong et al. 2003. PubMed ID: 12533788; Table S7, Gonzalez-Garay et al. 2013. PubMed ID: 24082139; Table1, Wu et al. 2006. PubMed ID: 16835864; Desrichard et al. 2011. PubMed ID: 22114986; Table S1, Susswein et al. 2015. PubMed ID: 26681312; Supp. Table 4, Kraus et al. 2016. PubMed ID: 27616075; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). Functional studies suggest this variant may negatively affect cellular response to DNA damage (Roeb. 2012. PubMed ID: 22419737) and partially reduce CHEK2 kinase activity (Wu et al. 2006. PubMed ID: 16835864). However, studies using a yeast functional assay to assess DNA damage response suggests this variant may be benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). An internal summary of amino acid substitution prediction programs gives conflicting predictions for the p.Glu64Lys change (Liu et al. 2016. PMID: 26555599). This variant has been observed in up to 0.03% of individuals of European (non-Finnish) descent in the gnomAD database. In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/128068/). Based on the current available evidence we classify this variant as likely pathogenic. (less)
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|
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Likely pathogenic
(Mar 16, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
True Health Diagnostics
Accession: SCV000805259.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Not Provided
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749676.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Likely pathogenic and reported on 01-08-2018 by Color. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Likely pathogenic and reported on 01-08-2018 by Color. 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:
Breast carcinoma (present)
Age: 50-59 years
Sex: female
Testing laboratory: Color Health, Inc
Date variant was reported to submitter: 2018-01-08
Testing laboratory interpretation: Likely pathogenic
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Hereditary Breast Carcinoma
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV000986765.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
Variant interpretted as Likely pathogenic and reported on 01/08/2018 by GTR ID Color. GenomeConnect assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpretted as Likely pathogenic and reported on 01/08/2018 by GTR ID Color. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Myopia (present) , Abnormality of the intestine (present) , Breast carcinoma (present)
Age: 50-59 years
Sex: female
Testing laboratory: Color Health, Inc
Date variant was reported to submitter: 2018-01-08
Testing laboratory interpretation: Likely pathogenic
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Comment:
Comment:
Variant summary: CHEK2 c.190G>A (p.Glu64Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251468 control chromosomes, predominantly at a frequency of 0.0003 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency of a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (0.00031), suggesting that it could be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, a high-homology CHEK2 pseudogene may confound these results and interpretation must be performed cautiously, allowing no conclusion about variant significance.c.190G>A has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (examples: Desrichard_2011, Susswein_2015, Kraus_2016, Shirts_2016, Carter_2018, Girard_2019, Kleiblova_2019, Tsaousis_2019, Hou_2020, Heygate_2020, Toss_2020, Rodriguez-Balada_2020, Vargas-Parra_2020, and Dorling 2021) without evidence for causality, but also in controls (examples: Girard_2019, Kleiblova_2019, and Dorling 2021). However, in at least one family study, 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals were reported, thus the variant did not co-segregate with disease (Kleiblova_2019). In addition, a recent case-control analysis showed that this variant is associated with breast cancer (Boonen_2022). The variant has also been reported in individuals with other cancer phenotypes, including colorectal cancer (examples- Susswein_2015, Rohlin_2016, Yurgelun_2017), prostate cancer (examples-Dong_2003, Wu_2006, Pritchard_2016, Abida_2017), and hereditary pancreatic cancer (example- Chaffee_2018). Several publications report experimental evidence evaluating an impact on protein function. Assays performed in yeast model systems have reported conflicting results: one study found that the variant impaired growth following DNA damage (Roeb_2012), while a similar study reported no significant impact on growth (Delimitsou_2019). Other laboratories have reported a reduction in CHEK2-specific phosphorylation and kinase activities in vitro (examples- Wu_2006, Kleiblova_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22419737, 12533788, 26681312, 16835864, 26845104, 22114986, 27621404, 27616075, 27433846, 27696107, 28135145, 28726808, 30851065, 30374176, 30447919, 30322717, 30303537, 31159747, 31398194, 31050813, 28825054, 31786208, 31980526, 32906215, 33471991, 32923877, 33919281, 34903604). Twenty-three ClinVar submitters have assessed the variant since 2014: fourteen classified the variant as uncertain significance and 9 as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
The p.E64K variant (also known as c.190G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 190. The glutamic acid at codon 64 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in multiple cohorts of breast, ovarian and prostate cancer patients (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Desrichard A et al. Breast Cancer Res. 2011;13:R119; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Tsai GJ et al. Genet. Med. 2019 06;21:1435-1442; Girard E et al. Int. J. Cancer. 2019 04;144:1962-1974). Functional studies conducted in multiple model systems have conflicting results as to the effect this protein has on substrate phosphorylation and DNA damage response (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Delimitsou A et al. Hum. Mutat. 2019 05;40:631-648; Kleiblova P et al. Int. J. Cancer. 2019 10;145:1782-1797; Boonen RACM et al. Cancer Res. 2022 Feb;82(4):615-631; Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). Although this variant may segregate incompletely with disease, co-segregation analysis should be used with extreme caution for genes with low relative risk like CHEK2 (Belman S et al. Genet. Med. 2020 Dec;22:2052-2059). This amino acid position is poorly conserved in available vertebrate species. Based on the available evidence, the clinical significance of this alteration remains unclear.
Comment:
This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was also shown to impact CHEK2 protein function (PMID 22419737). This variant occurs at a position that is moderately evolutionarily conserved and is predicted to be probably damaging by computer analysis with PolyPhen2 and SIFT. This analysis was performed in conjunction with the family studies as part of the University of Washington Find My Variant study.
Comment:
The CHEK2 c.190G>A (p.Glu64Lys) missense change has a maximum subpopulation frequency of 0.030% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant has been widely reported to be associated with cancer susceptibility (PMID: 12533788, 16835864, 16941491, 22114986, 24082139, 25503501, 26681312, 26845104, 26976419, 27433846, 27616075, 27696107, 27779110, 28135145, 31050813, 31220302). In a large breast cancer case-control analysis, the variant was enriched in breast cancer cases compared to controls (PMID: 33471991). It has also been reported in 11x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (http://whi.color.com). Large co-segregation studies have not been performed, however co-segregation in families is variable and the p.E64K has been observed in at least one individual who also harbored the p.I157T (PMID: 30374176, 31050813). Functional assays have reported that this variant results in reduced phosphorylation and partial disruption of CHEK2 kinase activity (PMID: 16835864, 31050813), however yeast-based DNA damage repair assays are inconclusive about a pathogenic or benign effect (PMID: 22419737, 30851065). In summary, this variant meets criteria to be classified as likely pathogenic with evidence suggesting lower penetrance.
Comment:
The missense variant c.190G>A (p.Glu64Lys) in CHEK2 gene has been reported in individuals with breast, ovarian, or prostate cancer (Dong ,et al., 2003) But other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Roeb, et al 2012).This variant has been reported to the ClinVar database as Uncertain Significance.The p.Glu64Lys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0001591 is reported in gnomAD. The amino acid Glu at position 64 is changed to a Lys changing protein sequence and it might alter its composition and physicochemical properties.In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu64Lys in CHEK2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 64 of the CHEK2 protein (p.Glu64Lys). This variant is present in population databases (rs141568342, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a personal and/or family history of breast, prostate, ovarian, colorectal, thyroid, and pancreatic cancer (PMID: 12533788, 22114986, 24082139, 26681312, 26845104, 27616075, 27779110, 28135145; Invitae; External communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128068). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16835864, 22419737). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
Neueste funkt. Daten von Stolarova et al. 2023 neutral in CHK2 assay intermediate in KAP1 Assay. Roeb 2012 kommt hier auf ein ´´damaging´´; Kleiblova 2019 auf ein ´´deleterious´´, Boonen 2021 kommt auf ein ´´intermediate´´ während Delimitosu 2019 die Veränderung als benign einstuft. Boonen et al diskutieren sehr schön die diskordanten Ergebnisse in Hefe und Mensch und zeigen noch ein weiteres Problem der Hefeassays auf, nämlich die Analyse bei 30 Grad statt 37 Grad, was natürlich Auswirkungen auf Proteinstabilitäten hat. Wu X, Dong X, Liu W, et al.: Characterization of CHEK2 mutations in prostate cancer. Hum Mutat 2006;27:742–7 ´´reduced autophosphorylation, CDC25C phosphorylation and severely impaired T68 phosphorylation´´. In der Arbeit von Dorling et al. (BRIDGES/BCAC) wurde die Variante 60X in 60.000 BC cases und 30X in 53.000 Kontrollen gefunden. Vgl. c.1100delC 868X in 60.000 cases und 254X in 53.000 Kontrollen.Evtl. handelt es sich um eine hypomorphe Variante
Comment:
Criteria applied: PS3,PS4_MOD
Comment:
Criteria applied: PS3,PS4_MOD
Comment:
BP4
Comment:
The CHEK2 c.190G>A; p.Glu64Lys variant (rs141568342) is reported in the literature in individuals with breast, ovarian, or prostate cancer (Carter 2018, Desrichard 2011, Dong 2003, Toss 2021). A yeast functional assay suggests this variant is benign (Delimitsou 2019), but other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Kleiblova 2019, Roeb 2012, Wu 2006). This variant is also reported by multiple laboratories in the ClinVar database (Variation ID: 128068) and is found in the general population with an overall allele frequency of 0.02% (45/282814 alleles) in the Genome Aggregation Database. The glutamate at codon 64 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.240). Given the currently available information, the clinical significance of this variant is uncertain at this time. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. 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. Dong X et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003 Feb;72(2):270-80. Epub 2003 Jan 17. PMID: 12533788. 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. 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. Toss A et al. Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers. Genes (Basel). 2021 Apr 21;12(5):616. PMID: 33919281. Wu X et al. Characterization of CHEK2 mutations in prostate cancer. Hum Mutat. 2006 Aug;27(8):742-7. PMID: 16835864.
Comment:
This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Comment:
In the published literature, this variant has been reported in individuals with prostate cancer (PMID: 12533788 (2003), 16941491 (2006), 24082139 (2013), 27433846 (2016), 28873162 (2017)), breast cancer and or ovarian cancer (PMID: 22419737 (2012), 25186627 (2015), 26976419 (2016), 26681312 (2016), 26845104 (2016), 27616075 (2016), 27779110 (2017), 28779002 (2017), 29555771 (2018), 30322717 (2018), 30303537 (2019), 31050813 (2019), 32923877 (2020), 31786208 (2020), 32805687 (2020), 33919281 (2021), 33471991 (2021)) and colorectal cancer (PMID: 28135145 (2017)). The variant has also been reported in healthy individuals (PMID: 26506619 (2015), 28779002 (2017), 30303537 (2019), 33471991 (2021)). Functional studies have reported conflicting results regarding the effect of this variant on CHEK2 protein function (PMID: 16835864 (2006), 22419737 (2012), 30851065 (2019)). The frequency of this variant in the general population, 0.00031 (16/50798 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces glutamic acid with lysine at codon 64 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). Multiple functional studies have shown this variant to disrupt CHEK2 function in kinase assays and DNA damage response (PMID: 16835864, 22419737, 31050813, 33606978, 34903604). One study has shown normal growth of yeast cells expressing the mutant protein following induction of DNA damage (PMID, 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 22114986, 25503501, 26681312, 26845104, 26976419, 27616075, 31050813, 33919281, 36011273, 36315097), colorectal cancer (PMID: 26681312, 27696107, 28135145), ovarian cancer (PMID: 26681312, 27779110), pancreatic cancer (PMID: 26845104), prostate cancer (PMID: 12533788, 16835864, 16941491, 24082139, 27433846, 31220302), and sarcoma (PMID: 35053600). In one study, breast cancer prevalence in women who carry this variant does not show statistically significant difference when compared to women who carry CHEK2 c.1100delC variant (PMID: 32805687). However, this variant has also been reported in two large breast cancer case-control meta-analyses, in 66/60466 cases and 33/53461 unaffected controls; OR=1.769 (95%CI 1.165 to 2.687); (Leiden Open Variation Database DB-ID CHEK2_000075) (PMID: 33471991), and 72/73048 cases and 29/88658 unaffected controls OR=3.0153 (95%CI 1.9592 to 4.6408); (PMID: 37449874). This variant has been identified in 45/282814 chromosomes (39/129148 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). This variant has also been identified in 11 of 9884 females over age 70 without personal history of cancer (FLOSSIES database, https://whi.color.com/variant/22-29130520-C-T). Based on the available evidence, this variant is classified as Likely Pathogenic. Although the penetrance of this variant has not been determined, its elevated frequency in the population and observations in unaffected individuals suggests that this variant may show reduced penetrance.
Comment:
Observed in individuals with CHEK2-related cancers with case-control comparisons supporting this variant is associated with breast cancer (PMID: 22419737, 34326862, 34903604, 37449874, 37839337); Published functional studies demonstrate intermediate to impaired auto-phosphorylation and kinase activity, with some conflicting results (PMID: 16835864, 22419737, 30851065, 31050813, 34903604, 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, 27616075, 28135145, 29522266, 27779110, 27433846, 31786208, 33919281, 35053600, 32906215, 22419737, 16835864, 24082139, 16941491, 22114986, 12533788, 27067391, 26976419, 26506619, 26845104, 27696107, 28135136, 27621404, 28726808, 28873162, 29555771, 29555025, 10973490, 30851065, 31050813, 31220302, 30322717, 31159747, 30303537, 30374176, 31101557, 32805687, 31980526, 32708810, 34426522, 34903604, 33606978, 32522261, 32923877, 35101071, 33047316, 33471991, 38061684, 34326862, 37449874, 36011273, 36315097, 35127508, 37507557, 37839337, 11733767)
Comment:
CHEK2: PS4, PS3:Moderate, BS2
Comment:
The CHEK2 p.Glu64Lys variant was identified in 16 of 30462 proband chromosomes (frequency: 0.0005) from individuals or families with breast, prostate, and colon cancer and was also identified in 1 of 1872 control chromosomes from healthy individuals (Desrichard 2011, Balmana 2016, Mandelker 2017, Susswein 2015, Rohlin 2016, Dong 2003, Wu 2006, Kraus 2017, Shirts 2016, Havranek 2015). The variant was also identified in dbSNP (ID: rs141568342) as "With Likely Pathogenic allele", in ClinVar (classified as likely pathogenic by GeneDx and a variant of uncertain significance by Ambry, Invitae, UWDLP, Counsyl and QDNISJC), and Zhejiang University database (3x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 44 of 277158 chromosomes at a frequency of 0.00016 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24020 chromosomes (freq: 0.00008), Latino in 2 of 34420 chromosomes (freq: 0.00006), European Non-Finnish in 38 of 126668 chromosomes (freq: 0.0003), and South Asian in 2 of 30782 chromosomes (freq: 0.00007). The variant was not observed in the “Other”, Ashkenazi Jewish, East Asian or Finnish populations. Functional analyses suggesting that this variant is pathogenic have shown reduced phosphorylation and kinase activity as well as loss of DNA damage response (Wu 2006, Roeb 2012). The p.Glu64Lys residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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:
The CHEK2 c.190G>A variant is predicted to result in the amino acid substitution p.Glu64Lys. This variant has been reported in individuals with a personal or family history of prostate, breast, ovarian, and colon cancer (Dong et al. 2003. PubMed ID: 12533788; Table S7, Gonzalez-Garay et al. 2013. PubMed ID: 24082139; Table1, Wu et al. 2006. PubMed ID: 16835864; Desrichard et al. 2011. PubMed ID: 22114986; Table S1, Susswein et al. 2015. PubMed ID: 26681312; Supp. Table 4, Kraus et al. 2016. PubMed ID: 27616075; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). Functional studies suggest this variant may negatively affect cellular response to DNA damage (Roeb. 2012. PubMed ID: 22419737) and partially reduce CHEK2 kinase activity (Wu et al. 2006. PubMed ID: 16835864). However, studies using a yeast functional assay to assess DNA damage response suggests this variant may be benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). An internal summary of amino acid substitution prediction programs gives conflicting predictions for the p.Glu64Lys change (Liu et al. 2016. PMID: 26555599). This variant has been observed in up to 0.03% of individuals of European (non-Finnish) descent in the gnomAD database. In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/128068/). Based on the current available evidence we classify this variant as likely pathogenic.
Comment:
Variant interpreted as Likely pathogenic and reported on 01-08-2018 by Color. 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.
Comment:
Variant interpretted as Likely pathogenic and reported on 01/08/2018 by GTR ID Color. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Comment:
Variant summary: CHEK2 c.190G>A (p.Glu64Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251468 control chromosomes, predominantly at a frequency of 0.0003 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency of a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (0.00031), suggesting that it could be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, a high-homology CHEK2 pseudogene may confound these results and interpretation must be performed cautiously, allowing no conclusion about variant significance.c.190G>A has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (examples: Desrichard_2011, Susswein_2015, Kraus_2016, Shirts_2016, Carter_2018, Girard_2019, Kleiblova_2019, Tsaousis_2019, Hou_2020, Heygate_2020, Toss_2020, Rodriguez-Balada_2020, Vargas-Parra_2020, and Dorling 2021) without evidence for causality, but also in controls (examples: Girard_2019, Kleiblova_2019, and Dorling 2021). However, in at least one family study, 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals were reported, thus the variant did not co-segregate with disease (Kleiblova_2019). In addition, a recent case-control analysis showed that this variant is associated with breast cancer (Boonen_2022). The variant has also been reported in individuals with other cancer phenotypes, including colorectal cancer (examples- Susswein_2015, Rohlin_2016, Yurgelun_2017), prostate cancer (examples-Dong_2003, Wu_2006, Pritchard_2016, Abida_2017), and hereditary pancreatic cancer (example- Chaffee_2018). Several publications report experimental evidence evaluating an impact on protein function. Assays performed in yeast model systems have reported conflicting results: one study found that the variant impaired growth following DNA damage (Roeb_2012), while a similar study reported no significant impact on growth (Delimitsou_2019). Other laboratories have reported a reduction in CHEK2-specific phosphorylation and kinase activities in vitro (examples- Wu_2006, Kleiblova_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22419737, 12533788, 26681312, 16835864, 26845104, 22114986, 27621404, 27616075, 27433846, 27696107, 28135145, 28726808, 30851065, 30374176, 30447919, 30322717, 30303537, 31159747, 31398194, 31050813, 28825054, 31786208, 31980526, 32906215, 33471991, 32923877, 33919281, 34903604). Twenty-three ClinVar submitters have assessed the variant since 2014: fourteen classified the variant as uncertain significance and 9 as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
The p.E64K variant (also known as c.190G>A), located in coding exon 1 of the CHEK2 gene, results from a G to A substitution at nucleotide position 190. The glutamic acid at codon 64 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in multiple cohorts of breast, ovarian and prostate cancer patients (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Desrichard A et al. Breast Cancer Res. 2011;13:R119; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Tsai GJ et al. Genet. Med. 2019 06;21:1435-1442; Girard E et al. Int. J. Cancer. 2019 04;144:1962-1974). Functional studies conducted in multiple model systems have conflicting results as to the effect this protein has on substrate phosphorylation and DNA damage response (Wu X et al. Hum. Mutat. 2006 Aug;27:742-7; Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Delimitsou A et al. Hum. Mutat. 2019 05;40:631-648; Kleiblova P et al. Int. J. Cancer. 2019 10;145:1782-1797; Boonen RACM et al. Cancer Res. 2022 Feb;82(4):615-631; Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). Although this variant may segregate incompletely with disease, co-segregation analysis should be used with extreme caution for genes with low relative risk like CHEK2 (Belman S et al. Genet. Med. 2020 Dec;22:2052-2059). This amino acid position is poorly conserved in available vertebrate species. Based on the available evidence, the clinical significance of this alteration remains unclear.
Comment:
This variant has been shown to partially reduce CHEK2 protein kinase activity (PMID 16835864). In a different functional assay system the CHEK2 p.E64K variant was also shown to impact CHEK2 protein function (PMID 22419737). This variant occurs at a position that is moderately evolutionarily conserved and is predicted to be probably damaging by computer analysis with PolyPhen2 and SIFT. This analysis was performed in conjunction with the family studies as part of the University of Washington Find My Variant study.
Comment:
The CHEK2 c.190G>A (p.Glu64Lys) missense change has a maximum subpopulation frequency of 0.030% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant has been widely reported to be associated with cancer susceptibility (PMID: 12533788, 16835864, 16941491, 22114986, 24082139, 25503501, 26681312, 26845104, 26976419, 27433846, 27616075, 27696107, 27779110, 28135145, 31050813, 31220302). In a large breast cancer case-control analysis, the variant was enriched in breast cancer cases compared to controls (PMID: 33471991). It has also been reported in 11x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (http://whi.color.com). Large co-segregation studies have not been performed, however co-segregation in families is variable and the p.E64K has been observed in at least one individual who also harbored the p.I157T (PMID: 30374176, 31050813). Functional assays have reported that this variant results in reduced phosphorylation and partial disruption of CHEK2 kinase activity (PMID: 16835864, 31050813), however yeast-based DNA damage repair assays are inconclusive about a pathogenic or benign effect (PMID: 22419737, 30851065). In summary, this variant meets criteria to be classified as likely pathogenic with evidence suggesting lower penetrance.
Comment:
The missense variant c.190G>A (p.Glu64Lys) in CHEK2 gene has been reported in individuals with breast, ovarian, or prostate cancer (Dong ,et al., 2003) But other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Roeb, et al 2012).This variant has been reported to the ClinVar database as Uncertain Significance.The p.Glu64Lys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.0001591 is reported in gnomAD. The amino acid Glu at position 64 is changed to a Lys changing protein sequence and it might alter its composition and physicochemical properties.In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu64Lys in CHEK2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 64 of the CHEK2 protein (p.Glu64Lys). This variant is present in population databases (rs141568342, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a personal and/or family history of breast, prostate, ovarian, colorectal, thyroid, and pancreatic cancer (PMID: 12533788, 22114986, 24082139, 26681312, 26845104, 27616075, 27779110, 28135145; Invitae; External communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128068). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 16835864, 22419737). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
Neueste funkt. Daten von Stolarova et al. 2023 neutral in CHK2 assay intermediate in KAP1 Assay. Roeb 2012 kommt hier auf ein ´´damaging´´; Kleiblova 2019 auf ein ´´deleterious´´, Boonen 2021 kommt auf ein ´´intermediate´´ während Delimitosu 2019 die Veränderung als benign einstuft. Boonen et al diskutieren sehr schön die diskordanten Ergebnisse in Hefe und Mensch und zeigen noch ein weiteres Problem der Hefeassays auf, nämlich die Analyse bei 30 Grad statt 37 Grad, was natürlich Auswirkungen auf Proteinstabilitäten hat. Wu X, Dong X, Liu W, et al.: Characterization of CHEK2 mutations in prostate cancer. Hum Mutat 2006;27:742–7 ´´reduced autophosphorylation, CDC25C phosphorylation and severely impaired T68 phosphorylation´´. In der Arbeit von Dorling et al. (BRIDGES/BCAC) wurde die Variante 60X in 60.000 BC cases und 30X in 53.000 Kontrollen gefunden. Vgl. c.1100delC 868X in 60.000 cases und 254X in 53.000 Kontrollen.Evtl. handelt es sich um eine hypomorphe Variante
Comment:
Criteria applied: PS3,PS4_MOD
Comment:
Criteria applied: PS3,PS4_MOD
Comment:
BP4
Comment:
The CHEK2 c.190G>A; p.Glu64Lys variant (rs141568342) is reported in the literature in individuals with breast, ovarian, or prostate cancer (Carter 2018, Desrichard 2011, Dong 2003, Toss 2021). A yeast functional assay suggests this variant is benign (Delimitsou 2019), but other functional assays report this variant causes reduced kinase activity and reduced DNA damage response (Kleiblova 2019, Roeb 2012, Wu 2006). This variant is also reported by multiple laboratories in the ClinVar database (Variation ID: 128068) and is found in the general population with an overall allele frequency of 0.02% (45/282814 alleles) in the Genome Aggregation Database. The glutamate at codon 64 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.240). Given the currently available information, the clinical significance of this variant is uncertain at this time. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. 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. Dong X et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003 Feb;72(2):270-80. Epub 2003 Jan 17. PMID: 12533788. 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. 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. Toss A et al. Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers. Genes (Basel). 2021 Apr 21;12(5):616. PMID: 33919281. Wu X et al. Characterization of CHEK2 mutations in prostate cancer. Hum Mutat. 2006 Aug;27(8):742-7. PMID: 16835864.
Comment:
This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Comment:
In the published literature, this variant has been reported in individuals with prostate cancer (PMID: 12533788 (2003), 16941491 (2006), 24082139 (2013), 27433846 (2016), 28873162 (2017)), breast cancer and or ovarian cancer (PMID: 22419737 (2012), 25186627 (2015), 26976419 (2016), 26681312 (2016), 26845104 (2016), 27616075 (2016), 27779110 (2017), 28779002 (2017), 29555771 (2018), 30322717 (2018), 30303537 (2019), 31050813 (2019), 32923877 (2020), 31786208 (2020), 32805687 (2020), 33919281 (2021), 33471991 (2021)) and colorectal cancer (PMID: 28135145 (2017)). The variant has also been reported in healthy individuals (PMID: 26506619 (2015), 28779002 (2017), 30303537 (2019), 33471991 (2021)). Functional studies have reported conflicting results regarding the effect of this variant on CHEK2 protein function (PMID: 16835864 (2006), 22419737 (2012), 30851065 (2019)). The frequency of this variant in the general population, 0.00031 (16/50798 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
This missense variant replaces glutamic acid with lysine at codon 64 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). Multiple functional studies have shown this variant to disrupt CHEK2 function in kinase assays and DNA damage response (PMID: 16835864, 22419737, 31050813, 33606978, 34903604). One study has shown normal growth of yeast cells expressing the mutant protein following induction of DNA damage (PMID, 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 22114986, 25503501, 26681312, 26845104, 26976419, 27616075, 31050813, 33919281, 36011273, 36315097), colorectal cancer (PMID: 26681312, 27696107, 28135145), ovarian cancer (PMID: 26681312, 27779110), pancreatic cancer (PMID: 26845104), prostate cancer (PMID: 12533788, 16835864, 16941491, 24082139, 27433846, 31220302), and sarcoma (PMID: 35053600). In one study, breast cancer prevalence in women who carry this variant does not show statistically significant difference when compared to women who carry CHEK2 c.1100delC variant (PMID: 32805687). However, this variant has also been reported in two large breast cancer case-control meta-analyses, in 66/60466 cases and 33/53461 unaffected controls; OR=1.769 (95%CI 1.165 to 2.687); (Leiden Open Variation Database DB-ID CHEK2_000075) (PMID: 33471991), and 72/73048 cases and 29/88658 unaffected controls OR=3.0153 (95%CI 1.9592 to 4.6408); (PMID: 37449874). This variant has been identified in 45/282814 chromosomes (39/129148 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). This variant has also been identified in 11 of 9884 females over age 70 without personal history of cancer (FLOSSIES database, https://whi.color.com/variant/22-29130520-C-T). Based on the available evidence, this variant is classified as Likely Pathogenic. Although the penetrance of this variant has not been determined, its elevated frequency in the population and observations in unaffected individuals suggests that this variant may show reduced penetrance.
Comment:
Observed in individuals with CHEK2-related cancers with case-control comparisons supporting this variant is associated with breast cancer (PMID: 22419737, 34326862, 34903604, 37449874, 37839337); Published functional studies demonstrate intermediate to impaired auto-phosphorylation and kinase activity, with some conflicting results (PMID: 16835864, 22419737, 30851065, 31050813, 34903604, 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, 27616075, 28135145, 29522266, 27779110, 27433846, 31786208, 33919281, 35053600, 32906215, 22419737, 16835864, 24082139, 16941491, 22114986, 12533788, 27067391, 26976419, 26506619, 26845104, 27696107, 28135136, 27621404, 28726808, 28873162, 29555771, 29555025, 10973490, 30851065, 31050813, 31220302, 30322717, 31159747, 30303537, 30374176, 31101557, 32805687, 31980526, 32708810, 34426522, 34903604, 33606978, 32522261, 32923877, 35101071, 33047316, 33471991, 38061684, 34326862, 37449874, 36011273, 36315097, 35127508, 37507557, 37839337, 11733767)
Comment:
CHEK2: PS4, PS3:Moderate, BS2
Comment:
The CHEK2 p.Glu64Lys variant was identified in 16 of 30462 proband chromosomes (frequency: 0.0005) from individuals or families with breast, prostate, and colon cancer and was also identified in 1 of 1872 control chromosomes from healthy individuals (Desrichard 2011, Balmana 2016, Mandelker 2017, Susswein 2015, Rohlin 2016, Dong 2003, Wu 2006, Kraus 2017, Shirts 2016, Havranek 2015). The variant was also identified in dbSNP (ID: rs141568342) as "With Likely Pathogenic allele", in ClinVar (classified as likely pathogenic by GeneDx and a variant of uncertain significance by Ambry, Invitae, UWDLP, Counsyl and QDNISJC), and Zhejiang University database (3x). The variant was not identified in Cosmic or MutDB databases. The variant was identified in control databases in 44 of 277158 chromosomes at a frequency of 0.00016 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 2 of 24020 chromosomes (freq: 0.00008), Latino in 2 of 34420 chromosomes (freq: 0.00006), European Non-Finnish in 38 of 126668 chromosomes (freq: 0.0003), and South Asian in 2 of 30782 chromosomes (freq: 0.00007). The variant was not observed in the “Other”, Ashkenazi Jewish, East Asian or Finnish populations. Functional analyses suggesting that this variant is pathogenic have shown reduced phosphorylation and kinase activity as well as loss of DNA damage response (Wu 2006, Roeb 2012). The p.Glu64Lys residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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:
The CHEK2 c.190G>A variant is predicted to result in the amino acid substitution p.Glu64Lys. This variant has been reported in individuals with a personal or family history of prostate, breast, ovarian, and colon cancer (Dong et al. 2003. PubMed ID: 12533788; Table S7, Gonzalez-Garay et al. 2013. PubMed ID: 24082139; Table1, Wu et al. 2006. PubMed ID: 16835864; Desrichard et al. 2011. PubMed ID: 22114986; Table S1, Susswein et al. 2015. PubMed ID: 26681312; Supp. Table 4, Kraus et al. 2016. PubMed ID: 27616075; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). Functional studies suggest this variant may negatively affect cellular response to DNA damage (Roeb. 2012. PubMed ID: 22419737) and partially reduce CHEK2 kinase activity (Wu et al. 2006. PubMed ID: 16835864). However, studies using a yeast functional assay to assess DNA damage response suggests this variant may be benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). An internal summary of amino acid substitution prediction programs gives conflicting predictions for the p.Glu64Lys change (Liu et al. 2016. PMID: 26555599). This variant has been observed in up to 0.03% of individuals of European (non-Finnish) descent in the gnomAD database. In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/128068/). Based on the current available evidence we classify this variant as likely pathogenic.
Comment:
Variant interpreted as Likely pathogenic and reported on 01-08-2018 by Color. 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.
Comment:
Variant interpretted as Likely pathogenic and reported on 01/08/2018 by GTR ID Color. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Profiling of the genetic features of patients with breast, ovarian, colorectal and extracolonic cancers: Association to CHEK2 and PALB2 germline mutations. | Infante M | Clinica chimica acta; international journal of clinical chemistry | 2024 | PMID: 38061684 |
| 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 |
| Multi-Gene Mutation Profiling by Targeted Next-Generation Sequencing in Premenopausal Breast Cancer. | Zografos E | Genes | 2022 | PMID: 36011273 |
| The Mutational Landscape of Early-Onset Breast Cancer: A Next-Generation Sequencing Analysis. | Andrikopoulou A | Frontiers in oncology | 2022 | PMID: 35127508 |
| Clinical Impact of Prospective Whole Genome Sequencing in Sarcoma Patients. | Schipper LJ | Cancers | 2022 | PMID: 35053600 |
| Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk. | Boonen RACM | Cancer research | 2022 | PMID: 34903604 |
| Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers. | Toss A | Genes | 2021 | PMID: 33919281 |
| Functional interrogation of DNA damage response variants with base editing screens. | Cuella-Martin R | Cell | 2021 | PMID: 33606978 |
| 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 |
| Pathogenic Variants in CHEK2 Are Associated With an Adverse Prognosis in Symptomatic Early-Onset Breast Cancer. | Greville-Heygate SL | JCO precision oncology | 2020 | PMID: 32923877 |
| Comprehensive analysis and ACMG-based classification of CHEK2 variants in hereditary cancer patients. | Vargas-Parra G | Human mutation | 2020 | PMID: 32906215 |
| Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing. | Sutcliffe EG | Cancer genetics | 2020 | PMID: 32805687 |
| Considerations in assessing germline variant pathogenicity using cosegregation analysis. | Belman S | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32773770 |
| Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging. | Hou YC | Proceedings of the National Academy of Sciences of the United States of America | 2020 | PMID: 31980526 |
| Identification of germline pathogenic variants in DNA damage repair genes by a next-generation sequencing multigene panel in BRCAX patients. | Rodríguez-Balada M | Clinical biochemistry | 2020 | PMID: 31786208 |
| 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 |
| Prognostic Significance of CHEK2 Mutation in Progression of Breast Cancer. | Ansari N | Laboratory medicine | 2019 | PMID: 31220302 |
| 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 |
| Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. | Tsai GJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30374176 |
| 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 |
| Prevalence of pathogenic variants and variants of unknown significance in patients at high risk of breast cancer: A systematic review and meta-analysis of gene-panel data. | van Marcke C | Critical reviews in oncology/hematology | 2018 | PMID: 30447919 |
| Germline pathogenic variants identified in women with ovarian tumors. | Carter NJ | Gynecologic oncology | 2018 | PMID: 30322717 |
| Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults. | Perkins BA | Proceedings of the National Academy of Sciences of the United States of America | 2018 | PMID: 29555771 |
| Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. | Chaffee KG | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28726808 |
| Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
| Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. | Abida W | JCO precision oncology | 2017 | PMID: 28825054 |
| Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. | Decker B | Journal of medical genetics | 2017 | PMID: 28779002 |
| 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 |
| 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 |
| Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing. | Rohlin A | Familial cancer | 2017 | PMID: 27696107 |
| Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. | Kraus C | International journal of cancer | 2017 | PMID: 27616075 |
| 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 |
| Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. | Pritchard CC | The New England journal of medicine | 2016 | PMID: 27433846 |
| A unified analytic framework for prioritization of non-coding variants of uncertain significance in heritable breast and ovarian cancer. | Mucaki EJ | BMC medical genomics | 2016 | PMID: 27067391 |
| Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. | Tung N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2016 | PMID: 26976419 |
| 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 |
| 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 |
| Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma. | Havranek O | PloS one | 2015 | PMID: 26506619 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. | Maxwell KN | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25503501 |
| 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 |
| Personalized genomic disease risk of volunteers. | Gonzalez-Garay ML | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 24082139 |
| 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 |
| Unique substitution of CHEK2 and TP53 mutations implicated in primary prostate tumors and cancer cell lines. | Zheng L | Human mutation | 2006 | PMID: 16941491 |
| Characterization of CHEK2 mutations in prostate cancer. | Wu X | Human mutation | 2006 | PMID: 16835864 |
| Mutations in CHEK2 associated with prostate cancer risk. | Dong X | American journal of human genetics | 2003 | PMID: 12533788 |
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Text-mined citations for rs141568342 ...
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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.