ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.7447A>G (p.Ser2483Gly)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.7447A>G (p.Ser2483Gly)
Variation ID: 52334 Accession: VCV000052334.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32356439 (GRCh38) [ NCBI UCSC ] 13: 32930576 (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 Apr 1, 2014 May 1, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.7447A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Ser2483Gly missense NC_000013.11:g.32356439A>G NC_000013.10:g.32930576A>G NG_012772.3:g.45960A>G LRG_293:g.45960A>G LRG_293t1:c.7447A>G LRG_293p1:p.Ser2483Gly U43746.1:n.7675A>G - Protein change
- S2483G
- Other names
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- Canonical SPDI
- NC_000013.11:32356438: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
18734 | 18892 |
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
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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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Uncertain significance (3) |
criteria provided, single submitter
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Aug 15, 2023 | RCV000113762.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2023 | RCV000164907.13 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000845281.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765135.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 28, 2023 | RCV000759654.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 27, 2022 | RCV001526974.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 7, 2023 | RCV003460611.1 |
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. |
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Uncertain significance
(Sep 28, 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: SCV000279489.9
First in ClinVar: May 29, 2016 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate that this variant results in cell survival similar to wild-type in assays evaluating ability to rescue BRCA2-null lethality and sensitivity to … (more)
Published functional studies demonstrate that this variant results in cell survival similar to wild-type in assays evaluating ability to rescue BRCA2-null lethality and sensitivity to DNA damaging agents (Biswas et al., 2020); Published splicing studies demonstrate this variant results in slightly disrupted splicing with the majority of transcripts being full-length while only a minority of transcripts lacked the first 12 nucleotides of exon 15 (Fraile-Bethencourt et al., 2019; Montalban et al., 2019); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7675A>G; This variant is associated with the following publications: (PMID: 19043619, 21523855, 11979449, 12955716, 16685647, 26913838, 31191615, 12228710, 30472649, 32522261, 31396961, 21735045, 31343793, 33293522) (less)
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Uncertain significance
(Aug 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004213693.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jan 18, 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: SCV001511368.4
First in ClinVar: Mar 14, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2483 of the BRCA2 protein (p.Ser2483Gly). … (more)
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2483 of the BRCA2 protein (p.Ser2483Gly). This variant is present in population databases (rs80358966, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer, esophageal squamous cell carcinoma, and/or ovarian cancer (PMID: 11979449, 12955716, 21735045, 31396961). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52334). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 33293522). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 31191615, 31343793; Invitae). 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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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Medulloblastoma Malignant tumor of prostate Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000896361.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Jun 27, 2022)
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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: SCV001737761.2
First in ClinVar: Jun 23, 2021 Last updated: Aug 03, 2022 |
Comment:
Variant summary: BRCA2 c.7447A>G (p.Ser2483Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: BRCA2 c.7447A>G (p.Ser2483Gly) results in a non-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. A computational method that produces a probabilistic likelihood ratio has predicted a neutral impact (Karchin_2008). 5/5 computational tools predict no significant impact on normal splicing at the canonical splice acceptor site although three tools predicted the creation of a new exonic acceptor site located 12 nucleotides downstream from the canonical splice acceptor site (Montalban_2019). At-least two studies reported a very low levels (10%) of transcript lacking 12 nucleotides from the 5' end of exon 15, while the majority of transcripts (90%) were full length (Montalban_2019, Fraile-Bethencourt_2019). However, the exact in-vivo consequences of these findings is not clear. The variant allele was found at a frequency of 1.6e-05 in 251306 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7447A>G has been reported in the literature in individuals from a Spanish family affected with breast cancer (Osorio_2002) that has been subsequently cited by others (Diez_2003, Montalban_2019) and in one case from a study of Esophageal squamous carcinoma in China (Ko_2020). Tumor analysis performed in the initial report from the Spanish family demonstrated retention of the wild-type allele and loss of the allele harbouring the variant confirming that the variant is not deleterious (Osorio_2002). 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 (Biswas_2020). These results showed "no damaging effect" of this variant in a mouse embryonic stem cell-based functional assay examining the ability to rescue the lethality of BRCA2 null mESC as well as sensitivity to six DNA damaging agents including ionizing radiation and a PARP inhibitor. This finding is consistent with the predominantly wild-type transcript pattern in the splicing assays summarized above. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all 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 VUS-possibly benign. (less)
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Uncertain significance
(Jun 14, 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: SCV000889125.3
First in ClinVar: Mar 14, 2019 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer or Lynch syndrome (PMIDs: 11979449 (2002), 12955716 (2003), 16685647 … (more)
In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer or Lynch syndrome (PMIDs: 11979449 (2002), 12955716 (2003), 16685647 (2006), 21735045 (2012), and 32522261 (2020)) and in an individual with Esophageal squamous carcinoma (PMID: 31396961 (2020)). Functional studies using cell survival and drug sensitivity assays showed that the variant is likely functional (PMID: 33293522 (2020)). In addition, other experimental studies reported that this variant resulted in only 10% of transcripts with an in-frame partial deletion of exon 15 while most of transcripts (90%) were full length (PMIDs: 31343793 (2019) and 31191615 (2019)). The frequency of this variant in the general population, 0.000087 (3/34572 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Jan 27, 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: SCV001359212.3
First in ClinVar: Mar 25, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces serine with glycine at codon 2483 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with glycine at codon 2483 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA2 function in Brca2-deficient mouse embryonic stem cells (PMID: 33293522). A RNA study reported that this variant resulted in 10% of transcripts with an in-frame partial deletion of exon 15 (resulting in the protein change Asp2479_Ser2483delinsGly). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11979449, 12955716, 16685647, 21735045), an individual with breast/ovarian cancer or Lynch syndrome (PMID: 32522261) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000190). This variant has been identified in 4/251306 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
(Aug 15, 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: SCV004844406.1
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 serine with glycine at codon 2483 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with glycine at codon 2483 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported that this variant does not impact BRCA2 function in Brca2-deficient mouse embryonic stem cells (PMID: 33293522). A RNA study reported that this variant resulted in 10% of transcripts with an in-frame partial deletion of exon 15 (resulting in the protein change Asp2479_Ser2483delinsGly). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11979449, 12955716, 16685647, 21735045), an individual with breast/ovarian cancer or Lynch syndrome (PMID: 32522261) and an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000190). This variant has been identified in 4/251306 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: 3
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Uncertain significance
(May 23, 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: SCV000215595.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.S2483G variant (also known as c.7447A>G), located in coding exon 14 of the BRCA2 gene, results from an A to G substitution at nucleotide … (more)
The p.S2483G variant (also known as c.7447A>G), located in coding exon 14 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7447. The serine at codon 2483 is replaced by glycine, an amino acid with similar properties. This variant has been reported in high risk breast cancer families and a high risk breast and ovarian cancer family (Osorio A et al. Int. J. Cancer. 2002 May;99:305-9; Weber F et al. Am. J. Hum. Genet. 2006 Jun;78:961-72; Menéndez M et al. Breast Cancer Res. Treat. 2012 Apr;132:979-92; Díez O et al. Hum. Mutat. 2003 Oct;22:301-12). One study found that this alteration results in incomplete use of this cryptic acceptor site, producing a transcript with the predicted in-frame deletion of 12 nucleotides in coding exon 14 (Fraile-Bethencourt E et al. Front Genet. 2019 May;10:503). However, other studies have found that this alteration does not result in a significant amount of aberrant splicing (Ambry internal data, Menéndez M et al. Breast Cancer Res. Treat. 2012 Apr;132:979-92). This amino acid position is poorly conserved in available vertebrate species. In addition, this amino acid change is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 02, 2020)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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BRCAlab, Lund University
Accession: SCV004243764.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000147090.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 2
Ethnicity/Population group: Caucasian
Geographic origin: Spain
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Uncertain significance
(Mar 01, 2019)
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no assertion criteria provided
Method: research
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Hereditary breast and ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology
Accession: SCV000916366.1
First in ClinVar: Sep 01, 2019 Last updated: Sep 01, 2019 |
Sex: female
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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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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 |
A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays. | Biswas K | NPJ genomic medicine | 2020 | PMID: 33293522 |
A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection. | Velázquez C | Journal of translational medicine | 2020 | PMID: 32522261 |
BRCA2 loss-of-function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese. | Ko JM | International journal of cancer | 2020 | PMID: 31396961 |
Incorporation of semi-quantitative analysis of splicing alterations for the clinical interpretation of variants in BRCA1 and BRCA2 genes. | Montalban G | Human mutation | 2019 | PMID: 31343793 |
Minigene Splicing Assays Identify 12 Spliceogenic Variants of BRCA2 Exons 14 and 15. | Fraile-Bethencourt E | Frontiers in genetics | 2019 | PMID: 31191615 |
Screening of BRCA1/2 deep intronic regions by targeted gene sequencing identifies the first germline BRCA1 variant causing pseudoexon activation in a patient with breast/ovarian cancer. | Montalban G | Journal of medical genetics | 2019 | PMID: 30472649 |
Assessing the RNA effect of 26 DNA variants in the BRCA1 and BRCA2 genes. | Menéndez M | Breast cancer research and treatment | 2012 | PMID: 21735045 |
Comprehensive prediction of mRNA splicing effects of BRCA1 and BRCA2 variants. | Mucaki EJ | Human mutation | 2011 | PMID: 21523855 |
Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios. | Karchin R | Cancer informatics | 2008 | PMID: 19043619 |
Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. | Weber F | American journal of human genetics | 2006 | PMID: 16685647 |
Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. | Díez O | Human mutation | 2003 | PMID: 12955716 |
Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer. | Osorio A | International journal of cancer | 2002 | PMID: 11979449 |
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Text-mined citations for rs80358966 ...
HelpRecord last updated Jun 02, 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.