ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7928C>T (p.Ala2643Val) (rs80359018)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575971 SCV000665140 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-05 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
Breast Cancer Information Core (BIC) (BRCA2) RCV000077015 SCV000147218 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Color RCV000575971 SCV000906943 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000589932 SCV000279980 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7928C>T at the cDNA level, p.Ala2643Val (A2643V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 8156C>T. This variant was identified in an unaffected control but absent from breast cancer cases (Wen 2018). BRCA2 Ala2643Val was not observed in large population cohorts (Lek 2016). This variant is located in within DSS1 contacting residue of 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 Ala2643Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589932 SCV000695107 uncertain significance not provided 2016-12-05 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7928C>T (p.Ala2643Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant is absent in 121376 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. 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 RCV000548871 SCV000635616 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 2643 of the BRCA2 protein (p.Ala2643Val). The alanine residue is moderately 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 a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 91498). An algorithm developed specifically for the BRCA2 gene (PMID: 19043619), suggests that this missense change is likely to be tolerated. However, this prediction has not been confirmed by published functional studies. In summary, this variant has uncertain impact on BRCA2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589932 SCV000889140 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077015 SCV000108812 uncertain significance Breast-ovarian cancer, familial 2 2012-05-17 no assertion criteria provided clinical testing

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