Submissions for variant NM_000059.4(BRCA2):c.6412G>T (p.Val2138Phe)

gnomAD frequency: 0.00346  dbSNP: rs11571659

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044938	SCV000072951	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000077373	SCV000154066	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-01-21	criteria provided, single submitter	literature only
Ambry Genetics	RCV000128955	SCV000172835	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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)	RCV000120342	SCV000225183	benign	not specified	2014-08-04	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077373	SCV000267796	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000311226	SCV000383744	likely benign	Fanconi anemia complementation group D1	2018-09-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000077373	SCV000383745	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2018-09-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000414271	SCV000492498	uncertain significance	Breast neoplasm		criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044938	SCV000494338	benign	Hereditary breast ovarian cancer syndrome	2014-09-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656613	SCV000602798	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128955	SCV000683781	likely benign	Hereditary cancer-predisposing syndrome	2015-03-10	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077373	SCV000744492	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120342	SCV000805743	benign	not specified	2017-03-20	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000044938	SCV002025798	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120342	SCV002070582	benign	not specified	2021-12-08	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000044938	SCV002515134	benign	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000128955	SCV002536232	benign	Hereditary cancer-predisposing syndrome	2021-04-26	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149687	SCV003838168	benign	Breast and/or ovarian cancer	2022-05-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000128955	SCV003852502	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	RCV000077373	SCV004844258	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing
ITMI	RCV000120342	SCV000084494	not provided	not specified	2013-09-19	no assertion provided	reference population
Sharing Clinical Reports Project (SCRP)	RCV000077373	SCV000109170	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077373	SCV000146846	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120342	SCV000592049	benign	not specified		no assertion criteria provided	clinical testing	The p.Val2138Phe variant has been identified in 4 out of 4579 proband chromosomes (frequency 0.001) in individuals with unilateral, contralateral and familial breast cancer phenotype, and also found in 1 out of 190 control chromosomes (frequency 0.005) included in these studies (Wagner 1999, Capanu 2011, Thesis (South African)). It is listed in dbSNP database coming from a “clinical source” (ID#: rs11571659) with a “global minor allele frequency of 0.001 (1000 genomes), therefore increasing the likelihood that this variant is benign. This residue is not highly conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. In the UMD database, this variant has been identified in 1 (out of 5) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 mutation was also detected, further suggesting that this is a benign variant. In addition, Myriad genetics has reported this variant as a polymorphism increasing the likelihood this variant is benign (personal communication). In summary, based on above information this variant is classified as Benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656613	SCV000778698	likely benign	not provided	2018-02-01	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120342	SCV001906324	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000656613	SCV001930621	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656613	SCV001953967	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000656613	SCV002035969	likely benign	not provided		no assertion criteria provided	clinical testing