Submissions for variant NM_000059.4(BRCA2):c.8807T>C (p.Leu2936Ser)

gnomAD frequency: 0.00005  dbSNP: rs398122714

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132403	SCV000187495	likely benign	Hereditary cancer-predisposing syndrome	2021-07-01	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	RCV000587247	SCV000210485	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Identified in an individual with breast cancer, but also in unaffected controls (Dorling et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9035T>C; This variant is associated with the following publications: (PMID: 12228710, 33471991, 31911673, 31853058, 32377563, 29884841)
Eurofins Ntd Llc (ga)	RCV000587247	SCV000227873	uncertain significance	not provided	2014-08-11	criteria provided, single submitter	clinical testing
Invitae	RCV000198146	SCV000254221	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000198146	SCV000267848	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-04-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000077643	SCV000488314	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132403	SCV000683999	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 2936 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 2/53461 unaffected controls (p-value=0.603) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008715). This variant has been identified in 7/282102 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160158	SCV000695183	uncertain significance	not specified	2019-10-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8807T>C (p.Leu2936Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250694 control chromosomes. 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.8807T>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587247	SCV000889168	uncertain significance	not provided	2023-06-19	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with ovarian cancer (PMID: 33526602 (2021)), and in several individuals in a hereditary cancer testing cohort (PMID: 31853058 (2020)). In a breast cancer association study, this variant was observed in an individual with breast cancer and as well as in two unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). In addition, this variant co-occurred with a pathogenic variant in the BRCA2 gene in an individual in our internal patient population, suggesting this variant was not the primary cause of disease. The frequency of this variant in the general population, 0.00024 (6/24936 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000132403	SCV002531975	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-12	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004528280	SCV004108468	uncertain significance	BRCA2-related disorder	2023-01-03	criteria provided, single submitter	clinical testing	The BRCA2 c.8807T>C variant is predicted to result in the amino acid substitution p.Leu2936Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32953506-T-C) and is interpreted as uncertain significance by the vast majority of clinical labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/91735/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003460732	SCV004213651	uncertain significance	Familial cancer of breast	2023-08-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077643	SCV004846072	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 2936 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control meta analysis conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 2/53461 unaffected controls (p-value=0.603) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008715). This variant has been identified in 7/282102 chromosomes 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.
Sharing Clinical Reports Project (SCRP)	RCV000077643	SCV000109446	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-09-19	no assertion criteria provided	clinical testing