ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4178C>T (p.Ala1393Val) (rs398122776)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165267 SCV000215983 likely benign Hereditary cancer-predisposing syndrome 2018-03-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000165267 SCV000903138 benign Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Counsyl RCV000410711 SCV000488362 uncertain significance Breast-ovarian cancer, familial 2 2016-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000074528 SCV000108613 likely benign not specified 2015-07-24 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.
Integrated Genetics/Laboratory Corporation of America RCV000587815 SCV000694748 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4178C>T (p.Ala1393Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/120260 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign and others classify it as a VUS, without evidence for independent evaluation. Taken together, this variant is classified as VUS until additional data becomes available.
Invitae RCV000472348 SCV000549793 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1393 of the BRCA2 protein (p.Ala1393Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs398122776, ExAC 0.01%). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 89047). 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.

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