ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1742C>T (p.Ser581Phe) (rs587778118)

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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 RCV000223160 SCV000278727 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000476382 SCV000549678 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 581 of the BRCA2 protein (p.Ser581Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 133726). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000120307 SCV001338259 uncertain significance not specified 2020-02-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1742C>T (p.Ser581Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251022 control chromosomes (gnomAD and publication). 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.1742C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI RCV000120307 SCV000084459 not provided not specified 2013-09-19 no assertion provided reference population

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