Submissions for variant NM_000059.3(BRCA2):c.943T>A (p.Cys315Ser) (rs79483201)

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Total submissions: 13

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130455	SCV000185320	benign	Hereditary cancer-predisposing syndrome	2015-05-08	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112866	SCV000145791	uncertain significance	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000769684	SCV000901097	likely benign	Breast and/or ovarian cancer	2016-05-18	criteria provided, single submitter	clinical testing
Color	RCV000130455	SCV000684062	likely benign	Hereditary cancer-predisposing syndrome	2015-06-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000112866	SCV000220522	likely benign	Breast-ovarian cancer, familial 2	2014-07-17	criteria provided, single submitter	literature only
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000160200	SCV000591720	likely benign	not specified	2016-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000160200	SCV000210551	benign	not specified	2016-06-21	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.
Illumina Clinical Services Laboratory,Illumina	RCV000402194	SCV000383620	likely benign	Fanconi anemia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000045821	SCV000383621	likely benign	Hereditary breast and ovarian cancer syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000160200	SCV000916903	likely benign	not specified	2018-06-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.943T>A (p.Cys315Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.943T>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, but it was also present in several healthy controls at the same time (e.g. Ahmad 2012, Haiman 2013, Suter 2004). Moreover, recent case-control studies performed on South-East Asian cohorts indicated that the variant of interest was found with similar frequencies in breast cancer patients and healthy controls (Lai 2017, Yoon 2016). Co-occurrences with other pathogenic variants have also been reported (e.g. BRCA1 c.3810C>A, p.Cys1270X; in UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. These laboratories classified the variant as benign (3x) or likely benign (4x). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV000045821	SCV000073834	benign	Hereditary breast and ovarian cancer syndrome	2018-01-12	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories,University of Michigan	RCV000112866	SCV000267741	likely benign	Breast-ovarian cancer, familial 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758976	SCV000887964	likely benign	not provided	2017-12-20	criteria provided, single submitter	clinical testing

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