Submissions for variant NM_000059.4(BRCA2):c.6513G>T (p.Val2171=)

dbSNP: rs206076

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000495019	SCV000579088	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
GeneDx	RCV000168590	SCV000210629	benign	not specified	2014-09-22	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	RCV000163332	SCV000213866	likely benign	Hereditary cancer-predisposing syndrome	2014-09-22	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)	RCV000724515	SCV000225154	uncertain significance	not provided	2017-02-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080322	SCV000253026	benign	Hereditary breast ovarian cancer syndrome	2025-01-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163332	SCV000683789	likely benign	Hereditary cancer-predisposing syndrome	2016-10-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000495019	SCV000786526	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-05-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724515	SCV000889100	benign	not provided	2023-01-17	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001080322	SCV002025801	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163332	SCV002536242	likely benign	Hereditary cancer-predisposing syndrome	2022-01-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000168590	SCV002761175	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149971	SCV003838170	likely benign	Breast and/or ovarian cancer	2022-04-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724515	SCV005093244	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BP7
Breakthrough Genomics, Breakthrough Genomics	RCV000724515	SCV005215525	likely benign	not provided		criteria provided, single submitter	not provided
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV005235050	SCV005880522	benign	Familial cancer of breast	2025-02-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353822	SCV000592060	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Val2171Val variant was not identified in the literature, but it was identified in dbSNP (ID: rs206076) “With benign, uncertain significance and untested allele”, Clinvitae database 4X, the ClinVar database with conflicting significance (1X as benign, 1X as likely benign and 2X as uncertain significance), UMD 2X an unknown variantand the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 4 of 10278 chromosomes (frequency: 0.00038) from a population of African individuals and in 3 of 66608 chromosomes (frequency: 4.50 X 10-3) from a population of 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified in our laboratory with a co-occurring pathogenic BRCA2 variant (p.Phe1559LeufsX9), increasing the likelihood that the p.Val2171Val variant does not have clinical significance. The p.Val2171Val 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 summary, based on the above information, we lean towards a more benign role for this variant. This variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004535037	SCV004756643	likely benign	BRCA2-related disorder	2019-06-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).