ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3578C>T (p.Ala1193Val) (rs431825310)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216169 SCV000275760 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-02 criteria provided, single submitter clinical testing The p.A1193V variant (also known as c.3578C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 3578. The alanine at codon 1193 is replaced by valine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000429172 SCV000526975 likely benign not specified 2016-04-25 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.
Invitae RCV000812976 SCV000953306 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-06-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1193 of the BRCA2 protein (p.Ala1193Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 96795). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000429172 SCV001337814 uncertain significance not specified 2020-01-14 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3578C>T (p.Ala1193Val) 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 was absent in 251042 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3578C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000216169 SCV001357019 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-19 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082916 SCV000114990 uncertain significance Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357751 SCV001553314 uncertain significance not provided no assertion criteria provided clinical testing The BRCA2 p.Ala1193Val variant was not identified in the literature nor was it identified in the LOVD 3.0, or UMD-LSDB, databases. The variant was identified in dbSNP (ID: rs431825310) as "With Uncertain significance allele", and in ClinVar (classified as likely benign by GeneDx; as uncertain significance by Ambry Genetics and SCRP). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ala1193 residue is not conserved in mammals and 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) 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. This variant is classified as a variant of uncertain significance.

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