Submissions for variant NM_000059.4(BRCA2):c.7630G>A (p.Gly2544Ser)

dbSNP: rs587781485

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129445	SCV000184215	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: 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.
Invitae	RCV000161933	SCV000211918	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2544 of the BRCA2 protein (p.Gly2544Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 141088). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 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.
Counsyl	RCV000662876	SCV000785774	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-11-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000656622	SCV000858442	uncertain significance	not provided	2017-12-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656622	SCV000883515	uncertain significance	not provided	2017-11-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781086	SCV000918898	likely benign	not specified	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7630G>A (p.Gly2544Ser) results in a non-conservative amino acid change located in the 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 was absent in 250832 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7630G>A has been reported to co-occur with another pathogenic variant in BRCA1 (BRCA1 c.3481_3491delGAAGATACTAG, p.Glu1161PhefsX3) in a clinical sample in the literature (example: Schenk_2017) as well as in one internal sample, providing supporting evidence for its benign role. The literature report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. In Homology-directed repair (HDR) activity, the variant was found to be functional (Richardson_2021, Hu_2022). The following publications have been ascertained in the context of this evaluation (PMID: 32377563, 35736817, 33609447, 28704513). Nine other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=7) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000656622	SCV001804775	likely benign	not provided	2021-04-29	criteria provided, single submitter	clinical testing	Not observed 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: 33609447, 32377563)
Genetic Services Laboratory, University of Chicago	RCV000781086	SCV002065626	uncertain significance	not specified	2017-11-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000656622	SCV003830141	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656622	SCV000778713	uncertain significance	not provided	2017-12-07	no assertion criteria provided	clinical testing