ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1513T>A (p.Ser505Thr)
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.
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.
Uncertain significance(3); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.1513T>A (p.Ser505Thr)
Variation ID: 182441 Accession: VCV000182441.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28689164 (GRCh38) [ NCBI UCSC ] 22: 29085152 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 19, 2017 May 1, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.1513T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Ser505Thr missense NM_001005735.2:c.1642T>A NP_001005735.1:p.Ser548Thr missense NM_001257387.2:c.850T>A NP_001244316.1:p.Ser284Thr missense NM_001349956.2:c.1312T>A NP_001336885.1:p.Ser438Thr missense NM_145862.2:c.1426T>A NP_665861.1:p.Ser476Thr missense NC_000022.11:g.28689164A>T NC_000022.10:g.29085152A>T NG_008150.2:g.57703T>A LRG_302:g.57703T>A LRG_302t1:c.1513T>A LRG_302p1:p.Ser505Thr - Protein change
- S505T, S284T, S438T, S476T, S548T
- Other names
- p.S505T:TCC>ACC
- Canonical SPDI
- NC_000022.11:28689163:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4045 | 4100 |
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
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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. |
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Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2021 | RCV000160441.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 22, 2023 | RCV000212471.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 17, 2024 | RCV000476991.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 1, 2019 | RCV001030619.2 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 7, 2021 | RCV001193688.3 |
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. |
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Likely benign
(Jun 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362700.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2021 |
Comment:
Variant summary: CHEK2 c.1513T>A (p.Ser505Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: CHEK2 c.1513T>A (p.Ser505Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 281104 control chromosomes, predominantly at a frequency of 0.00083 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. While CHEK2 does have highly homologous pseudogenes, the surrounding region of the variant appears to be unaffected by pseudogene interference via BLAT search. c.1513T>A has been reported in the literature in case control cohorts of Japanese individuals affected with breast cancer and in ethnicity matched unaffected controls (example, Momozawa_2018, Fujita_2020) as well as in settings of multigene panel testing for breast cancer (example, Tung_2015). One of these publications has recently reported a final clinical significance for this variant as "benign" using the ACMG/AMP guidelines (Fujita_2020). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a yeast based experimental system evaluating the ability to resume cell growth and proliferation by repair of methyl-methanesulfonate (MMS) induced DNA damage (Delimitsou_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Aug 04, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002537388.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Jul 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134159.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
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Likely benign
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000215797.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(May 01, 2019)
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criteria provided, single submitter
Method: research
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Hereditary breast and ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Cancer Genomics Group, Japanese Foundation For Cancer Research
Accession: SCV001193553.2
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
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Likely benign
(Oct 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000684606.4
First in ClinVar: Feb 19, 2018 Last updated: Jun 19, 2021 |
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Uncertain significance
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000210995.17
First in ClinVar: Feb 24, 2015 Last updated: Aug 31, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: cell growth and proliferation after … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: cell growth and proliferation after DNA damage similar to wild type (Delimitsou et al., 2019); Observed in individuals with breast cancer (Tung et al., 2015; Momozawa et al., 2018; Xie et al., 2018); Also known as c.1642T>A p.(S548T); Not observed at significant frequency in large population cohorts (gnomAD); Observed in colorectal cancer cases and in controls at similar allele frequencies (Fujita et al., 2020); This variant is associated with the following publications: (PMID: 15942682, 25186627, 28580595, 30287823, 30851065, 32566746, 33309985) (less)
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Uncertain significance
(Jan 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000550549.11
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 505 of the CHEK2 protein (p.Ser505Thr). … (more)
This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 505 of the CHEK2 protein (p.Ser505Thr). This variant is present in population databases (rs587781960, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 28580595, 30287823). This variant is also known as c.1642T>A (p.Ser548Thr). ClinVar contains an entry for this variant (Variation ID: 182441). 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 does not substantially affect CHEK2 function (PMID: 30851065). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Population-based Screening for Hereditary Colorectal Cancer Variants in Japan. | Fujita M | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2022 | PMID: 33309985 |
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 |
Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Mutation screening of 10 cancer susceptibility genes in unselected breast cancer patients. | Xie Y | Clinical genetics | 2018 | PMID: 28580595 |
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 |
Aberrations of the CHK2 gene are rare in pediatric solid tumors. | Chen YY | International journal of molecular medicine | 2005 | PMID: 15942682 |
Text-mined citations for rs587781960 ...
HelpRecord last updated Jul 15, 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.