Variant summary: CHEK2 c.1555C>T (p.Arg519X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.3e-06 in 232840 control chromosomes (gnomAD). c.1555C>T has been reported in the literature in multiple individuals affected with colon cancer, prostate cancer, breast cancer and/or ovarian cancer (Yorczyk_2014, Maxwell_2014, Susswein_2015, Velho_2019, Ryu_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) and likely pathogenic (5x). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1555C>T (p.Arg519Ter)
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.
(20)
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.
Pathogenic/Likely pathogenic
20
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007194.4(CHEK2):c.1555C>T (p.Arg519Ter)
Variation ID: 128064 Accession: VCV000128064.52
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q12.1 22: 28687974 (GRCh38) [ NCBI UCSC ] 22: 29083962 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 20, 2016 Nov 30, 2024 Oct 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_007194.4:c.1555C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Arg519Ter nonsense NM_001005735.2:c.1684C>T NP_001005735.1:p.Arg562Ter nonsense NM_001257387.2:c.892C>T NP_001244316.1:p.Arg298Ter nonsense NM_001349956.2:c.1354C>T NP_001336885.1:p.Arg452Ter nonsense NM_145862.2:c.1468C>T NP_665861.1:p.Arg490Ter nonsense NC_000022.11:g.28687974G>A NC_000022.10:g.29083962G>A NG_008150.2:g.58893C>T LRG_302:g.58893C>T LRG_302t1:c.1555C>T LRG_302p1:p.Arg519Ter - Protein change
- R519*, R562*, R490*, R298*, R452*
- Other names
-
p.R519*:CGA>TGA
- Canonical SPDI
- NC_000022.11:28687973:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 25, 2023 | RCV000116005.21 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 11, 2017 | RCV000210124.6 | |
| Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 2, 2024 | RCV000212474.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 19, 2020 | RCV000589100.5 | |
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV000471222.19 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 1, 2024 | RCV001705822.5 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 17, 2020 | RCV001798352.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2021 | RCV003162543.3 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
- | RCV004796022.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000786152.2
First in ClinVar: May 26, 2018 Last updated: May 26, 2018 |
|
|
|
Likely pathogenic
(Jul 11, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Breast and colorectal cancer, susceptibility to
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266167.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
|
|
|
Pathogenic
(Nov 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast and ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698785.2
First in ClinVar: Mar 17, 2018 Last updated: Dec 07, 2020 |
Comment:
Variant summary: CHEK2 c.1555C>T (p.Arg519X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: CHEK2 c.1555C>T (p.Arg519X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.3e-06 in 232840 control chromosomes (gnomAD). c.1555C>T has been reported in the literature in multiple individuals affected with colon cancer, prostate cancer, breast cancer and/or ovarian cancer (Yorczyk_2014, Maxwell_2014, Susswein_2015, Velho_2019, Ryu_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) and likely pathogenic (5x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Sep 17, 2020)
|
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: SCV002043396.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
|
|
|
Pathogenic
(Jun 07, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002537393.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The CHEK2 c.1555C>T (p.R519X) variant has been reported in heterozygosity in multiple individuals with breast, uterine, prostate, and colorectal cancer (PMID: 30680046, 29020732, 25503501, 27751358, … (more)
The CHEK2 c.1555C>T (p.R519X) variant has been reported in heterozygosity in multiple individuals with breast, uterine, prostate, and colorectal cancer (PMID: 30680046, 29020732, 25503501, 27751358, 29520813). This nonsense variant creates a premature stop codon at residue 519 of the CHEK2 protein. As this variant is not predicted to cause nonsense-mediated decay, the protein product is expected to be truncated. This variant was observed in 1/10138 chromosomes in the Ashkenazi Jewish population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 128065). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
|
Likely pathogenic
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470305.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 06, 2024 |
Comment:
The CHEK2 c.1555C>T (p.Arg519*) variant is not predicted to cause nonsense-mediated decay, however it may negatively impact protein function due to the partial loss of … (more)
The CHEK2 c.1555C>T (p.Arg519*) variant is not predicted to cause nonsense-mediated decay, however it may negatively impact protein function due to the partial loss of the nuclear localization signal that is located within the truncated 25 amino acids (PMID: 24879340 (2014), 22419737 (2012), 12909615 (2003)). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32805687 (2020), 32761968 (2020), 30287823 (2018), 25503501 (2015), 25318351 (2014)), ovarian cancer (PMID: 29020732 (2018), prostate cancer (PMID: 29520813 (2018)), and colorectal cancer (PMID: 26681312 (2015)). The frequency of this variant in the general population, 0.000099 (1/10138 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. (less)
|
|
|
Pathogenic
(Sep 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000689671.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 15 of the CHEK2 gene, creating a premature translation stop signal in the last coding exon. The mutant … (more)
This variant changes 1 nucleotide in exon 15 of the CHEK2 gene, creating a premature translation stop signal in the last coding exon. The mutant transcript is likely to escape nonsense-mediated decay and expressed as a truncated protein that lacks the functionally important nuclear localization signal (PMID: 12909615, 16798742, 24879340). This variant has been reported in seven individuals affected with breast cancer, including two individuals having a family history of breast or colorectal cancer (PMID: 25503501, 25318351, 30287823; Color internal data) and in an individual affected with ovarian cancer with a family history colorectal cancer (PMID: 29020732). This variant has also been reported individuals affected with uterine cancer (PMID: 30680046) and prostate cancer (PMID: 29520813), and in four unaffected individuals (PMID: 30287823). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000215386.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.R519* pathogenic mutation (also known as c.1555C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at … (more)
The p.R519* pathogenic mutation (also known as c.1555C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1555. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration occurs at the 3' terminus of theCHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 25 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data; Zannini L et al. J. Biol. Chem. 2003 Oct;278:42346-51). This mutation has been reported in the literature in breast cancer and prostate cancer cohorts (Yorczyk A et al. Clin. Genet. 2015 Sep;88:278-82; Maxwell K et al. Genet. Med. 2015 Aug;17:630-8; Wu Y et al. Prostate 2018 06;78(8):607-615; Fonfria M et al. J Pers Med 2021 Jun;11(6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004217492.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Mar 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934497.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
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: SCV004020188.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
|
|
|
Likely pathogenic
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breast Care Center, Daerim St. Mary`s Hospital
Accession: SCV004021929.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
The CHEK2:c.1555C>T (p.Arg519*) variant was located in the last coding exon 15 of the CHEK2 gene, which predicts a truncation to lead to a nonsense … (more)
The CHEK2:c.1555C>T (p.Arg519*) variant was located in the last coding exon 15 of the CHEK2 gene, which predicts a truncation to lead to a nonsense codon, resulting in a null variant. This type of variant is a known mechanism of disease. It was rarely reported in the gnomAD population database. This likely pathogenic variant was detected in a 73-year-old Korean female diagnosed with hormone-positive and invasive breast cancer. The patient had a first-degree family member with pancreatic cancer in their 70s. (less)
Indication for testing: Hereditary Breast and Ovarian Cancer
Age: 70-79 years
Sex: female
Ethnicity/Population group: East Asian
Geographic origin: South Korea
|
|
|
Likely pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000550494.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg519*) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg519*) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the CHEK2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 25186627, 25503501, 27751358, 29020732, 29520813, 30287823, 30680046, 32761968). ClinVar contains an entry for this variant (Variation ID: 128064). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 34903604). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the nuclear localization signal (NLS) of the CHEK2 protein, which is critical for proper nuclear localization (PMID: 18004398, 12909615). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. 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
(Jul 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149914.16
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation, as the last 25 amino acids are lost, and other loss-of-function variants have been reported downstream in … (more)
Nonsense variant predicted to result in protein truncation, as the last 25 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, ovarian, prostate, and other cancers (PMID: 25503501, 25186627, 25318351, 32832836, 32761968, 35118230); Published functional studies are inconclusive: demonstrate intermediate impact on phosphorylation compared to wildtype (PMID: 34903604); This variant is associated with the following publications: (PMID: 26681312, 29520813, 12909615, 24879340, 33309985, 36243179, 25503501, 25318351, 27751358, 29020732, 18004398, 29308099, 25186627, 30680046, 30287823, 30293905, 35273153, 32805687, 32832836, 32980694, 32761968, 34204722, 32322110, 32172797, 35118230, 32019277, 36988593, 31650100, 35643632, 38575974, 22419737, 38898688, 34903604) (less)
|
|
|
Likely pathogenic
(Oct 01, 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: SCV001934350.2
First in ClinVar: Sep 26, 2021 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PVS1_STR, PS4_MOD, PM2_SUP
Clinical Features:
Breast carcinoma (present)
Sex: female
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 2
Bone osteosarcoma Familial prostate cancer
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
germline
|
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005415898.1
First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024 |
Comment:
PVS1_Strong+PM2_Supporting+PS4
|
|
|
Pathogenic
(Jul 01, 2021)
|
no assertion criteria provided
Method: research
|
Gastric cancer
Affected status: unknown
Allele origin:
germline
|
Laboratory for Genotyping Development, RIKEN
Accession: SCV002758512.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978188.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979566.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
|
|
Pathogenic
(Aug 26, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
BRCAlab, Lund University
Accession: SCV002588979.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
|
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Comment:
Comment:
The CHEK2 c.1555C>T (p.Arg519*) variant is not predicted to cause nonsense-mediated decay, however it may negatively impact protein function due to the partial loss of the nuclear localization signal that is located within the truncated 25 amino acids (PMID: 24879340 (2014), 22419737 (2012), 12909615 (2003)). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32805687 (2020), 32761968 (2020), 30287823 (2018), 25503501 (2015), 25318351 (2014)), ovarian cancer (PMID: 29020732 (2018), prostate cancer (PMID: 29520813 (2018)), and colorectal cancer (PMID: 26681312 (2015)). The frequency of this variant in the general population, 0.000099 (1/10138 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Comment:
This variant changes 1 nucleotide in exon 15 of the CHEK2 gene, creating a premature translation stop signal in the last coding exon. The mutant transcript is likely to escape nonsense-mediated decay and expressed as a truncated protein that lacks the functionally important nuclear localization signal (PMID: 12909615, 16798742, 24879340). This variant has been reported in seven individuals affected with breast cancer, including two individuals having a family history of breast or colorectal cancer (PMID: 25503501, 25318351, 30287823; Color internal data) and in an individual affected with ovarian cancer with a family history colorectal cancer (PMID: 29020732). This variant has also been reported individuals affected with uterine cancer (PMID: 30680046) and prostate cancer (PMID: 29520813), and in four unaffected individuals (PMID: 30287823). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.R519* pathogenic mutation (also known as c.1555C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1555. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration occurs at the 3' terminus of theCHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 25 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data; Zannini L et al. J. Biol. Chem. 2003 Oct;278:42346-51). This mutation has been reported in the literature in breast cancer and prostate cancer cohorts (Yorczyk A et al. Clin. Genet. 2015 Sep;88:278-82; Maxwell K et al. Genet. Med. 2015 Aug;17:630-8; Wu Y et al. Prostate 2018 06;78(8):607-615; Fonfria M et al. J Pers Med 2021 Jun;11(6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
The CHEK2:c.1555C>T (p.Arg519*) variant was located in the last coding exon 15 of the CHEK2 gene, which predicts a truncation to lead to a nonsense codon, resulting in a null variant. This type of variant is a known mechanism of disease. It was rarely reported in the gnomAD population database. This likely pathogenic variant was detected in a 73-year-old Korean female diagnosed with hormone-positive and invasive breast cancer. The patient had a first-degree family member with pancreatic cancer in their 70s.
Comment:
This sequence change creates a premature translational stop signal (p.Arg519*) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the CHEK2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 25186627, 25503501, 27751358, 29020732, 29520813, 30287823, 30680046, 32761968). ClinVar contains an entry for this variant (Variation ID: 128064). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 34903604). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the nuclear localization signal (NLS) of the CHEK2 protein, which is critical for proper nuclear localization (PMID: 18004398, 12909615). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. 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:
Nonsense variant predicted to result in protein truncation, as the last 25 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, ovarian, prostate, and other cancers (PMID: 25503501, 25186627, 25318351, 32832836, 32761968, 35118230); Published functional studies are inconclusive: demonstrate intermediate impact on phosphorylation compared to wildtype (PMID: 34903604); This variant is associated with the following publications: (PMID: 26681312, 29520813, 12909615, 24879340, 33309985, 36243179, 25503501, 25318351, 27751358, 29020732, 18004398, 29308099, 25186627, 30680046, 30287823, 30293905, 35273153, 32805687, 32832836, 32980694, 32761968, 34204722, 32322110, 32172797, 35118230, 32019277, 36988593, 31650100, 35643632, 38575974, 22419737, 38898688, 34903604)
Comment:
Criteria applied: PVS1_STR, PS4_MOD, PM2_SUP
Comment:
PVS1_Strong+PM2_Supporting+PS4
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:
Variant summary: CHEK2 c.1555C>T (p.Arg519X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.3e-06 in 232840 control chromosomes (gnomAD). c.1555C>T has been reported in the literature in multiple individuals affected with colon cancer, prostate cancer, breast cancer and/or ovarian cancer (Yorczyk_2014, Maxwell_2014, Susswein_2015, Velho_2019, Ryu_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) and likely pathogenic (5x). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The CHEK2 c.1555C>T (p.Arg519*) variant is not predicted to cause nonsense-mediated decay, however it may negatively impact protein function due to the partial loss of the nuclear localization signal that is located within the truncated 25 amino acids (PMID: 24879340 (2014), 22419737 (2012), 12909615 (2003)). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32805687 (2020), 32761968 (2020), 30287823 (2018), 25503501 (2015), 25318351 (2014)), ovarian cancer (PMID: 29020732 (2018), prostate cancer (PMID: 29520813 (2018)), and colorectal cancer (PMID: 26681312 (2015)). The frequency of this variant in the general population, 0.000099 (1/10138 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Comment:
This variant changes 1 nucleotide in exon 15 of the CHEK2 gene, creating a premature translation stop signal in the last coding exon. The mutant transcript is likely to escape nonsense-mediated decay and expressed as a truncated protein that lacks the functionally important nuclear localization signal (PMID: 12909615, 16798742, 24879340). This variant has been reported in seven individuals affected with breast cancer, including two individuals having a family history of breast or colorectal cancer (PMID: 25503501, 25318351, 30287823; Color internal data) and in an individual affected with ovarian cancer with a family history colorectal cancer (PMID: 29020732). This variant has also been reported individuals affected with uterine cancer (PMID: 30680046) and prostate cancer (PMID: 29520813), and in four unaffected individuals (PMID: 30287823). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The p.R519* pathogenic mutation (also known as c.1555C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1555. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration occurs at the 3' terminus of theCHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 25 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data; Zannini L et al. J. Biol. Chem. 2003 Oct;278:42346-51). This mutation has been reported in the literature in breast cancer and prostate cancer cohorts (Yorczyk A et al. Clin. Genet. 2015 Sep;88:278-82; Maxwell K et al. Genet. Med. 2015 Aug;17:630-8; Wu Y et al. Prostate 2018 06;78(8):607-615; Fonfria M et al. J Pers Med 2021 Jun;11(6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
The CHEK2:c.1555C>T (p.Arg519*) variant was located in the last coding exon 15 of the CHEK2 gene, which predicts a truncation to lead to a nonsense codon, resulting in a null variant. This type of variant is a known mechanism of disease. It was rarely reported in the gnomAD population database. This likely pathogenic variant was detected in a 73-year-old Korean female diagnosed with hormone-positive and invasive breast cancer. The patient had a first-degree family member with pancreatic cancer in their 70s.
Comment:
This sequence change creates a premature translational stop signal (p.Arg519*) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the CHEK2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 25186627, 25503501, 27751358, 29020732, 29520813, 30287823, 30680046, 32761968). ClinVar contains an entry for this variant (Variation ID: 128064). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 34903604). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the nuclear localization signal (NLS) of the CHEK2 protein, which is critical for proper nuclear localization (PMID: 18004398, 12909615). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. 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:
Nonsense variant predicted to result in protein truncation, as the last 25 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, ovarian, prostate, and other cancers (PMID: 25503501, 25186627, 25318351, 32832836, 32761968, 35118230); Published functional studies are inconclusive: demonstrate intermediate impact on phosphorylation compared to wildtype (PMID: 34903604); This variant is associated with the following publications: (PMID: 26681312, 29520813, 12909615, 24879340, 33309985, 36243179, 25503501, 25318351, 27751358, 29020732, 18004398, 29308099, 25186627, 30680046, 30287823, 30293905, 35273153, 32805687, 32832836, 32980694, 32761968, 34204722, 32322110, 32172797, 35118230, 32019277, 36988593, 31650100, 35643632, 38575974, 22419737, 38898688, 34903604)
Comment:
Criteria applied: PVS1_STR, PS4_MOD, PM2_SUP
Comment:
PVS1_Strong+PM2_Supporting+PS4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
| CHEK2 variants: linking functional impact to cancer risk. | Boonen RACM | Trends in cancer | 2022 | PMID: 35643632 |
| Clinical and genomic features of Chinese lung cancer patients with germline mutations. | Peng W | Nature communications | 2022 | PMID: 35273153 |
| Clinical Utility of Germline Genetic Testing in Japanese Men Undergoing Prostate Biopsy. | Akamatsu S | JNCI cancer spectrum | 2022 | PMID: 35118230 |
| Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk. | Boonen RACM | Cancer research | 2022 | PMID: 34903604 |
| Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes. | Mizukami K | EBioMedicine | 2020 | PMID: 32980694 |
| Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing. | Sutcliffe EG | Cancer genetics | 2020 | PMID: 32805687 |
| Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer. | Ryu JS | Cancer science | 2020 | PMID: 32761968 |
| Molecular Characterization and Clinical Outcomes of Primary Gleason Pattern 5 Prostate Cancer After Radical Prostatectomy. | Velho PI | JCO precision oncology | 2019 | PMID: 31650100 |
| Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes. | Henn J | Hereditary cancer in clinical practice | 2019 | PMID: 30680046 |
| Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
| A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. | Wu Y | The Prostate | 2018 | PMID: 29520813 |
| Detection of Germline Mutations in Patients with Epithelial Ovarian Cancer Using Multi-gene Panels: Beyond BRCA1/2. | Eoh KJ | Cancer research and treatment | 2018 | PMID: 29020732 |
| Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers. | Leedom TP | Cancer genetics | 2016 | PMID: 27751358 |
| Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
| Prevalence of 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 |
| Use of panel tests in place of single gene tests in the cancer genetics clinic. | Yorczyk A | Clinical genetics | 2015 | PMID: 25318351 |
| 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 |
| Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures. | Ow GS | Cell cycle (Georgetown, Tex.) | 2014 | PMID: 24879340 |
| Response to DNA damage of CHEK2 missense mutations in familial breast cancer. | Roeb W | Human molecular genetics | 2012 | PMID: 22419737 |
| CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? | Antoni L | Nature reviews. Cancer | 2007 | PMID: 18004398 |
| Intrinsic kinase activity and SQ/TQ domain of Chk2 kinase as well as N-terminal domain of Wip1 phosphatase are required for regulation of Chk2 by Wip1. | Yoda A | The Journal of biological chemistry | 2006 | PMID: 16798742 |
| Karyopherin-alpha2 protein interacts with Chk2 and contributes to its nuclear import. | Zannini L | The Journal of biological chemistry | 2003 | PMID: 12909615 |
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Text-mined citations for rs200432447 ...
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Record last updated Nov 30, 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.