Submissions for variant NM_000059.4(BRCA2):c.2145A>G (p.Gly715=)

gnomAD frequency: 0.00056  dbSNP: rs112566179

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495123	SCV000578023	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 0.0014 (African), derived from ExAC (2014-12-17).
GeneDx	RCV000160214	SCV000210575	benign	not specified	2014-06-22	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	RCV000162803	SCV000213284	likely benign	Hereditary cancer-predisposing syndrome	2014-07-10	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	RCV001079130	SCV000252606	benign	Hereditary breast ovarian cancer syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162803	SCV000683470	benign	Hereditary cancer-predisposing syndrome	2015-09-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000160214	SCV000861269	likely benign	not specified	2018-05-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477574	SCV000889005	benign	not provided	2022-07-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000160214	SCV002065573	benign	not specified	2021-04-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162803	SCV002533298	likely benign	Hereditary cancer-predisposing syndrome	2021-06-30	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001079130	SCV004228095	benign	Hereditary breast ovarian cancer syndrome	2023-08-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000495123	SCV004847014	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	RCV000495123	SCV001549664	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The BRCA2 p.Gly715= variant was identified in 1 of 820 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Fackenthal 2012). The variant was also identified in dbSNP (ID: rs112566179) as "With other allele", ClinVar (classified as benign by Invitae, GeneDx, Color and ENIGMA; as likely benign by three submitters), LOVD 3.0 (3x), and in UMD-LSDB (4x as unclassified variant). The variant was identified in UMD-LSDB with a co-occurring pathogenic BRCA2 variant (c.6159delT, p.Ala2054Leufs*16), increasing the likelihood that the p.Gly715= variant does not have clinical significance. The variant was identified in control databases in 43 of 277062 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 42 of 24028 chromosomes (freq: 0.002) and Latino in 1 of 34366 chromosomes (freq: 0.00003), while the variant was not observed in the Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Gly715= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.