ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8354C>T (p.Pro2785Leu) (rs786202034)

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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 RCV000164641 SCV000215305 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000412223 SCV000487831 uncertain significance Breast-ovarian cancer, familial 2 2015-11-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779934 SCV000916875 uncertain significance not specified 2018-03-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8354C>T (p.Pro2785Leu) results in a non-conservative amino acid change located in the OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246210 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.8354C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000821790 SCV000962562 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2785 of the BRCA2 protein (p.Pro2785Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. 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: 185253). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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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