ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7933A>G (p.Arg2645Gly)
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(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.7933A>G (p.Arg2645Gly)
Variation ID: 230994 Accession: VCV000230994.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32362650 (GRCh38) [ NCBI UCSC ] 13: 32936787 (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 Feb 19, 2018 May 1, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.7933A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Arg2645Gly missense NC_000013.11:g.32362650A>G NC_000013.10:g.32936787A>G NG_012772.3:g.52171A>G LRG_293:g.52171A>G LRG_293t1:c.7933A>G LRG_293p1:p.Arg2645Gly - Protein change
- R2645G
- Other names
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- Canonical SPDI
- NC_000013.11:32362649:A:G
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18807 | 18965 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Nov 17, 2023 | RCV000222813.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 26, 2021 | RCV000759664.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 28, 2024 | RCV000552479.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 13, 2023 | RCV003997876.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 23, 2023 | RCV001193806.2 |
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
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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
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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
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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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Uncertain significance
(Aug 26, 2021)
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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: SCV000889141.4
First in ClinVar: Mar 14, 2019 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 23, 2023)
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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: SCV001362934.2
First in ClinVar: Jun 22, 2020 Last updated: Nov 20, 2023 |
Comment:
Variant summary: BRCA2 c.7933A>G (p.Arg2645Gly) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of the … (more)
Variant summary: BRCA2 c.7933A>G (p.Arg2645Gly) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 254522 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7933A>G has been reported in the literature in individuals affected with Hereditary Breast and/or Ovarian Cancer Syndrome (e.g. Caputo_2021), colorectal cancer (e.g. Dobbins_2016), or prostate cancer (e.g. Darst_2021) without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22505045, 34597585, 32853339, 27356891, 35260348). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Nov 17, 2023)
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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: SCV000683917.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glycine at codon 2645 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with glycine at codon 2645 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 27356891), an individual affected with prostate cancer (PMID: 32853339), and in a multifactorial analysis with family history, pathology and segregation likelihood ratios for pathogenicity of 0.24, 0.05, and 2.93, respectively (PMID: 34597585). This variant has been identified in 3/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000635619.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2645 of the BRCA2 protein (p.Arg2645Gly). … (more)
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2645 of the BRCA2 protein (p.Arg2645Gly). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 22505045, 27356891, 32853339, 34597585). ClinVar contains an entry for this variant (Variation ID: 230994). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Studies have shown that this missense change does not affect mRNA splicing (PMID: 22505045). 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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Likely benign
(Jan 05, 2022)
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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: SCV000274714.7
First in ClinVar: May 29, 2016 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
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004845574.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces arginine with glycine at codon 2645 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces arginine with glycine at codon 2645 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 27356891), an individual affected with prostate cancer (PMID: 32853339), and in a multifactorial analysis with family history, pathology and segregation likelihood ratios for pathogenicity of 0.24, 0.05, and 2.93, respectively (PMID: 34597585). This variant has been identified in 3/251304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
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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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Hereditary Cancer Gene Variants in Hispanic Men With a Personal or Family History of Prostate Cancer. | Ramamurthy C | Clinical genitourinary cancer | 2022 | PMID: 35260348 |
Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach. | Caputo SM | American journal of human genetics | 2021 | PMID: 34597585 |
Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer. | Darst BF | Journal of the National Cancer Institute | 2021 | PMID: 32853339 |
Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes. | Dobbins SE | Familial cancer | 2016 | PMID: 27356891 |
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. | Houdayer C | Human mutation | 2012 | PMID: 22505045 |
Text-mined citations for rs876658889 ...
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.