ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8059G>T (p.Val2687Phe)

dbSNP: rs80359044
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212269 SCV000210460 uncertain significance not provided 2022-07-21 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 2915G>T; This variant is associated with the following publications: (PMID: 19043619, 12228710, 24013206, 33609447, 29884841)
Ambry Genetics RCV000571107 SCV000668620 likely pathogenic Hereditary cancer-predisposing syndrome 2024-03-06 criteria provided, single submitter clinical testing The p.V2687F variant (also known as c.8059G>T), located in coding exon 17 of the BRCA2 gene, results from a G to T substitution at nucleotide position 8059. The valine at codon 2687 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet. Med., 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468). Based on internal structural assessment, this alteration disrupts the structure of the OB1 domain, near the interface with DSS (Yang H et al. Science, 2002 Sep;297:1837-48; Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001346741 SCV001540967 uncertain significance Hereditary breast ovarian cancer syndrome 2023-09-17 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29884841, 33609447). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function. ClinVar contains an entry for this variant (Variation ID: 52491). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033, 21520333). This variant is present in population databases (rs80359044, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2687 of the BRCA2 protein (p.Val2687Phe).
PreventionGenetics, part of Exact Sciences RCV004528252 SCV004110536 likely pathogenic BRCA2-related disorder 2023-01-19 criteria provided, single submitter clinical testing The BRCA2 c.8059G>T variant is predicted to result in the amino acid substitution p.Val2687Phe. Functional prediction programs have evaluated the the p.Val2687Phe change (also referred to as V2687F) as damaging (Supplementary Table S2, Hart et al. 2018. PubMed ID: 29884841; Supplementary Table 1, Karchin et al. 2008. PubMed ID: 19043619). This variant was shown to significantly reduce homology-directed repair (HDR) using the well-known in vitro DR-GFP assay, and was classified as a loss of function variant (Richardson et al. 2021. PubMed ID: 33609447). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32937398-G-T). In ClinVar, this variant has conflicting interpretations, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/52491). Taken together, we interpret this variant as likely pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113863 SCV000147261 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2003-12-23 no assertion criteria provided clinical testing

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