Submissions for variant NM_000059.4(BRCA2):c.8972G>A (p.Arg2991His)

gnomAD frequency: 0.00002  dbSNP: rs80359150

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086948	SCV000073689	benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131351	SCV000186326	likely benign	Hereditary cancer-predisposing syndrome	2019-03-29	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	RCV001719712	SCV000518105	likely benign	not provided	2021-05-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19043619, 17899372, 20507642, 22632462, 26554728, 29394989, 30254663, 29884841, 33609447)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000435349	SCV000695198	benign	not specified	2021-10-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8972G>A (p.Arg2991His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250784 control chromosomes, predominantly at a frequency of 0.00041 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.4e-05 vs 0.00075), allowing no conclusion about variant significance. c.8972G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Zuntini_2018, Dorling_2021, Guo_2020), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported from publicly available databses (BRCA2 c.5645C>A, p.Ser1882X; BRCA2 c.9924C>G, p.Tyr3308X), providing supporting evidence for a benign role. Two independent studies showed the variant to have functional HDR activity (Guidugli_2018, Richardson_2021) and one study reported the variant to have no impact on splicing (Whiley_2010). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five labs classified the variant as likely bening/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001086948	SCV000890986	likely benign	Hereditary breast ovarian cancer syndrome	2021-08-26	criteria provided, single submitter	clinical testing	The BRCA2 c.8972G>A (p.Arg2991His) missense change has a maximum subpopulation frequency of 0.040% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/13-32953905-G-A). In silico tools are not in agreement about effect of this variant on protein function, however in vitro functional studies have shown that this variant results in an activity comparable to the wild type in homology-directed DNA repair (HDR) assays (BS3; PMID: 29394989). This variant has been reported in two women older than 70 years of age who have never had cancer (BS2_supporting; https://whi.color.com/variant/13-32953905-G-A). It has also been reported in an individual with breast or ovarian cancer (PMID: 30254663). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS3, BS2_supporting.
Color Diagnostics, LLC DBA Color Health	RCV000131351	SCV000910894	likely benign	Hereditary cancer-predisposing syndrome	2015-10-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000435349	SCV001470464	benign	not specified	2020-01-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131351	SCV002531995	likely benign	Hereditary cancer-predisposing syndrome	2021-06-09	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031783	SCV000054391	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-01-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031783	SCV000147505	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000031783	SCV004228456	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Strong)+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)