Submissions for variant NM_000059.4(BRCA2):c.7462A>G (p.Arg2488Gly)

dbSNP: rs746057464

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529176	SCV000635578	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2488 of the BRCA2 protein (p.Arg2488Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22425665, 26997744, 30362333, 33067490). This variant is also known as 7690A>G. ClinVar contains an entry for this variant (Variation ID: 462440). 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: 29394989, 35736817). 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.
Ambry Genetics	RCV001026467	SCV001188853	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.
Color Diagnostics, LLC DBA Color Health	RCV001026467	SCV001344651	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 2488 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study reported this variant to be neutral based on a homology-directed DNA repair assay (PMID: 29394989). This variant has been observed in two individuals affected with breast cancer (PMID: 26997744, 30362333) and an individual affected with early-onset or familiar breast/ovarian cancer (PMID: 22425665). This variant has not been identified 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.
GeneDx	RCV001591221	SCV001823995	likely benign	not provided	2020-02-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30362333, 33067490, 29884841, 29394989, 30263132, 28814288, 23697973, 26997744, 22425665)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001591221	SCV005625283	uncertain significance	not provided	2024-11-02	criteria provided, single submitter	clinical testing	The BRCA2 c.7462A>G (p.Arg2488Gly) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 35402282 (2022), 33067490 (2020), 30362333 (2018), 26997744 (2016), 22425665 (2012), 23697973 (2012)). It has also been identified in affected individuals, but not in any reportedly healthy individuals in a large-scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). This variant has been reported to have no deleterious effect on BRCA2 homologous directed DNA repair (HDR) activity (PMIDs: 29394989 (2018), 35736817 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Medical and Surgical Sciences, University of Bologna	RCV003483661	SCV004228436	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BS3(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)