Submissions for variant NM_000059.4(BRCA2):c.1911T>C (p.Gly637=)

gnomAD frequency: 0.00109  dbSNP: rs11571652

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495455	SCV000578010	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 0.04; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0048 (African), derived from ExAC (2014-12-17).
GeneDx	RCV000173955	SCV000167337	benign	not specified	2014-02-25	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	RCV000163054	SCV000213548	likely benign	Hereditary cancer-predisposing syndrome	2014-09-25	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.
Eurofins Ntd Llc (ga)	RCV000173955	SCV000225149	benign	not specified	2015-02-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084147	SCV000261104	benign	Hereditary breast ovarian cancer syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000474400	SCV000541059	benign	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163054	SCV000683461	benign	Hereditary cancer-predisposing syndrome	2016-01-06	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000495455	SCV000744421	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000173955	SCV000805658	benign	not specified	2017-05-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757036	SCV000885082	benign	not provided	2022-05-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000173955	SCV000888993	benign	not specified	2022-03-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000173955	SCV002065675	likely benign	not specified	2018-09-12	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV001084147	SCV002515254	likely benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000163054	SCV002533278	benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000173955	SCV002550297	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353538	SCV000591782	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Gly637Gly variant was identified in 2 of 4206 proband chromosomes (frequency: 0.0000) from individuals or families with hereditary breast and ovarian cancer (Edwards 2003). In addition, the variant was found in one paper classifying BRCA2 mutations in prostate cancer, where it was classified as a polymorphism (Borg 2010). The variant was also identified in dbSNP (ID: rs11571652) “With likely benign allele” and “uncertain significance allele”, with a minor allele frequency of 0.0024 (1000 Genomes Project, Clinvitae database, the ClinVar database (classified as a benign variant GeneDx and Emory Genetics Laboratory and classified as “likely benign” by Ambry Genetics), GeneInsight COGR database(1X, classified as “unknown significance” by a clinical laboratory), the BIC database (1X with unknown clinical importance), and UMD (4X as an unknown variant). This variant was also identified in the Exome Variant Server project in 19 of 4406 African American alleles (frequency: 0.004), and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 47 of 9796 chromosomes (frequency: 0.0048) from a population of African individuals, as well as at lower frequencies Latino and European (non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Gly637Gly variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000495455	SCV000745676	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-21	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000757036	SCV001905753	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000173955	SCV001978350	benign	not specified		no assertion criteria provided	clinical testing