Submissions for variant NM_000059.4(BRCA2):c.8421G>A (p.Ser2807=)

gnomAD frequency: 0.00003  dbSNP: rs371278843

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000409819	SCV000578018	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0028 (South Asian), derived from ExAC (2014-12-17).
GeneDx	RCV000160251	SCV000210669	benign	not specified	2014-10-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000163212	SCV000213735	likely benign	Hereditary cancer-predisposing syndrome	2014-11-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085334	SCV000252615	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000409819	SCV000488659	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163212	SCV000683966	likely benign	Hereditary cancer-predisposing syndrome	2015-10-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758961	SCV000887941	benign	not provided	2019-03-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160251	SCV001158087	benign	not specified	2018-12-31	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001085334	SCV002504865	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163212	SCV002531944	likely benign	Hereditary cancer-predisposing syndrome	2021-03-31	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492646	SCV004240364	likely benign	Breast and/or ovarian cancer	2023-05-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000409819	SCV004845656	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353520	SCV000592190	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Ser2807Ser variant was not identified in the literature. The variant was identified in dbSNP (ID: rs371278843) “With Likely benign allele”, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, the ClinVar database (classified as a benign variant by GeneDx; classified as likely benign by Ambry Genetics), GeneInsight COGR database (1X, classified as “likely benign” by a clinical laboratory), and UMD (1X as a UV variant). This variant was identified in the Exome Variant Server project in 1 of 4406 African American alleles, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015). The variant was also identified in 46 of 16508 individuals from South Asia (frequency: 0.0028) and once in homozygous state, increasing the likelihood this variant does not have clinical significance. It was also identified in one East Asian and one African individual, increasing the likelihood this could be a low frequency benign variant in certain populations of origin. The p.Ser2807Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. It should be noted that another variant at the same position (c.8421G>T, p.Ser2807Ser) did not show splicing aberration and classified as Class 2, likely not pathogenic, according to the IARC 5 class system (Thomassen 2012). In summary, based on the above information this variant is classified as benign.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000758961	SCV001906060	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000758961	SCV001953442	likely benign	not provided		no assertion criteria provided	clinical testing