Submissions for variant NM_000059.4(BRCA2):c.7751G>A (p.Gly2584Asp)

dbSNP: rs80359001

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131991	SCV000187049	likely benign	Hereditary cancer-predisposing syndrome	2020-02-25	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000485049	SCV000566871	likely benign	not provided	2021-04-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19043619, 29394989, 29988080, 29884841, 33609447)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001371400	SCV001567961	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2584 of the BRCA2 protein (p.Gly2584Asp). This variant is present in population databases (rs80359001, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033, 21520333). ClinVar contains an entry for this variant (Variation ID: 52398). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29988080, 33609447). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281734	SCV002572031	uncertain significance	not specified	2022-08-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7751G>A (p.Gly2584Asp) results in a non-conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) 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 4e-06 in 251428 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7751G>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. Several independent publications have reported experimental evidence confirming that the variant is functional in vitro. One study using a Brca2-null mouse embryonic stem cell complementation assay showed the variant had 70% of the HDR activity seen in wild-type (Mesman_2018). Others have confirmed the variant retains HDR activity via complementation assays using different BRCA2-null cell lines (Guidugli_2018, Richardson_2021). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as likely benign and one as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Myriad Genetics, Inc.	RCV000113811	SCV004043188	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485049	SCV005625294	uncertain significance	not provided	2024-01-04	criteria provided, single submitter	clinical testing	The BRCA2 c.7751G>A (p.Gly2584Asp) variant has been reported in the published literature in functional studies as not damaging to protein function (PMIDs: 29394989 (2018), 29988080 (2018), and 33609447 (2021)). The frequency of this variant in the general population, 0.000004 (1/251428 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113811	SCV000147170	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing