ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8450G>T (p.Cys2817Phe) (rs786201992)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164566 SCV000215224 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000164566 SCV000689127 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000506092 SCV000918860 uncertain significance not specified 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The c.8450G>T (p.Cys2817Phe) in BRCA2 gene is a missense variant involves a highly conserved nucleotide and 5/5 in silico tools used predict deleterious outcome. The variant is located within the second OB fold (OB2) functional domain, however no functional studies confirming an effect of this change on the protein function were published at the time of evaluation. The variant is present in the control population dataset of gnomAD (0.000004; 1/246186 chrs tested), which does not exceed the maximal expected allele frequency for a disease causing allele in BRCa2 gene (0.00075). The variant has been reported in at least one affected individual with personal and family history of BrC, who also carried a pathogenic variant in BRCA1 (Tung_2015) as well as in healthy controls (FlOSSIES db), and is cited as VUS by a reputable databases/clinical laboratories. Taken together,due to lack of segregatiaon data for the reported affected individuals, the variant was classified as VUS, until new information becomes available.
Invitae RCV000229582 SCV000283342 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 2817 of the BRCA2 protein (p.Cys2817Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. 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: 185196). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506092 SCV000600805 uncertain significance not specified 2017-03-22 criteria provided, single submitter clinical testing

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