ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8825C>A (p.Ala2942Asp) (rs373227180)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166381 SCV000217173 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
GeneDx RCV000160159 SCV000210486 uncertain significance not provided 2018-02-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8825C>A at the cDNA level, p.Ala2942Asp (A2942D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCT>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 9053C>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala2942Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ala2942Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781101 SCV000918932 uncertain significance not specified 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8825C>A (p.Ala2942Asp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/245636 control chromosomes in gnomAD at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000693651 SCV000821528 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 2942 of the BRCA2 protein (p.Ala2942Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs373227180, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182256). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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