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

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045821	SCV000073834	benign	Hereditary breast and ovarian cancer syndrome	2020-12-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130455	SCV000185320	benign	Hereditary cancer-predisposing syndrome	2015-05-08	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
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.
Counsyl	RCV000112866	SCV000220522	likely benign	Breast-ovarian cancer, familial 2	2014-07-17	criteria provided, single submitter	literature only
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
Illumina Clinical Services Laboratory,Illumina	RCV000402194	SCV000383620	likely benign	Fanconi anemia, complementation group D1	2017-04-27	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 Clinical Services Laboratory,Illumina	RCV000112866	SCV000383621	likely benign	Breast-ovarian cancer, familial 2	2019-09-30	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.
Color Health, Inc	RCV000130455	SCV000684062	likely benign	Hereditary cancer-predisposing syndrome	2015-06-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758976	SCV000887964	benign	not provided	2018-09-18	criteria provided, single submitter	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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160200	SCV000916903	benign	not specified	2020-09-25	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 variant allele was found at a frequency of 0.0005 in 238344 control chromosomes, predominantly at a frequency of 0.0054 within the East Asian subpopulation in the gnomAD database. 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 Syndrome 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 sequencing studies of 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). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Numerous reported co-occurrences with other pathogenic variant(s) have been reported in the BIC and UMD databases (captured verbatim from the database records, BIC - BRCA2 c.5946_5946delT, p.Ser1982Argfs; BRCA1 c.1687C>T, p.Gln563Ter; BRCA1 c.4035_4035delA, p.Glu1345=fs; BRCA1 c.5263_5264insC, p.Ser1755?fs; BRCA1 c.4148C>G, p.Ser1383Ter; UMD - BRCA1 c.3810C>A, p.Cys1270Ter), providing supporting evidence for a benign role. No experimental evidence demonstrating an impact on protein function was ascertained in the context of this classification. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=4)/likely benign (n=7). Some submitters cite overlapping evidences utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000758976	SCV001148971	likely benign	not provided	2018-04-01	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
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000758976	SCV000591720	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Cys315Ser variant was identified in 1 of 74 proband chromosomes (frequency: 0.014) from individuals or families with hereditary breast and ovarian cancer (Toh 2008) and in 4 of 534 proband chromosomes (frequency: 0.007) from individuals or families with esophageal cancer (Akbari 2008, Hu 2004). The variant was also identified in dbSNP (ID: rs79483201) as “other,” Clinvitae database (with conflicting interpretations by multiple submitters the ClinVar database (1X as “benign,” 3X as “likely benign,” and 2X as “uncertain significance”), the BIC database (15X with unknown clinical importance), and UMD (14X as ”unclassified variant”). The variant was not found in the Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database, COSMIC, or GeneInsight COGR databases. This variant was identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.0016) and in the Exome Aggregation Consortium database (March 14, 2016) in 45 of 120310 chromosomes (freq. 0.0004) in the following populations: East Asian in 44 of 8626 chromosomes (freq. 0.005), South Asian in 1 of 16236 chromosomes (freq. 0.000006), but was not seen in African, Finnish, European (Non-Finnish), and Latino populations, increasing the likelihood this could be a low frequency benign variant. The p.Cys315 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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 at the known exon/intron boundary however 3 out of 5 programs suggest a change in a 3’ cryptic splice site. Akbari (2008) classified the variant as deleterious because it is located in the region implicated in the BRCA2-P/CAF complex formation. Hu (2004) classified the variant as uncertain significance because although the variant showed segregation in the families studied, they could not demonstrate co-segregation with disease. In addition, this variant was previously identified by our laboratory in an individual as co-occurring with a pathogenic BRCA2 variant c.8961_8964delGAGT increasing the likelihood that the p.Cys315Ser variant does not have clinical significance. 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000758976	SCV001798102	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute	RCV000758976	SCV001906263	likely benign	not provided		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000758976	SCV001958529	likely benign	not provided		no assertion criteria provided	clinical testing