Submissions for variant NM_000059.4(BRCA2):c.2957A>G (p.Asn986Ser)

gnomAD frequency: 0.00006  dbSNP: rs28897718

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080867	SCV000072106	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129122	SCV000183839	likely benign	Hereditary cancer-predisposing syndrome	2018-05-25	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	RCV000586870	SCV000210583	likely benign	not provided	2020-05-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20104584, 25682074, 23929434, 27882345, 21520273)
Counsyl	RCV000113119	SCV000488650	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168561	SCV000694656	likely benign	not specified	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2957A>G (p.Asn986Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 249782 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (5.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.2957A>G has been reported in the literature in individuals affected with Breast Cancer (example, Borg 2008, Capanu_2011, Wong-Brown 2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been reported in the BIC database (BRCA2 c.2808_2811delACAA, p.Lys936_Gln937?fs), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Biswas_2020). These results showed no damaging effect of this variant based on probability of impact on function (PIF) of variants based on cell survival (HAT) and drug sensitivity (DS) assay results individually and combined (HAT +DS). The following publications have been ascertained in the context of this evaluation (PMID: 33293522, 20104584, 21520273, 23929434, 25682074). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=5; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000129122	SCV000902858	benign	Hereditary cancer-predisposing syndrome	2016-09-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586870	SCV001133729	uncertain significance	not provided	2018-10-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000168561	SCV001160379	uncertain significance	not specified	2019-03-07	criteria provided, single submitter	clinical testing	The BRCA2 c.2957A>G; p.Asn986Ser variant (rs28897718) is reported in the literature in several individuals affected with breast cancer, although its clinical significance was not determined in these studies (Borg 2010, Wong-Brown 2015). This variant is reported in ClinVar (Variation ID: 51377), and it is found in the non-Finnish European population with an overall allele frequency of 0.01% (13/128448 alleles) in the Genome Aggregation Database. The asparagine at codon 986 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Asn986Ser variant is uncertain at this time. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Wong-Brown MW et al. Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. Breast Cancer Res Treat. 2015 Feb;150(1):71-80.
Mayo Clinic Laboratories, Mayo Clinic	RCV000586870	SCV001716147	uncertain significance	not provided	2019-04-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129122	SCV002533750	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129122	SCV003850268	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000113119	SCV004845088	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113119	SCV000146146	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735534	SCV000863672	uncertain significance	Breast and/or ovarian cancer	2002-09-19	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541233	SCV004790725	uncertain significance	BRCA2-related disorder	2024-01-09	no assertion criteria provided	clinical testing	The BRCA2 c.2957A>G variant is predicted to result in the amino acid substitution p.Asn986Ser. This variant has been documented in patients with breast cancer from large cohort studies (Supp. Table S3, Borg et al. 2010. PubMed ID: 20104584; Supplementary Table, Capanu et al. 2011. PubMed ID: 21520273; Supplementary Table 2, Wong-Brown et al. 2015. PubMed ID: 25682074). However, further clinical or functional evidence was not provided to assess the pathogenicity of this variant. This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity ranging from benign to uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/51377). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.