ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2203C>G (p.Leu735Val) (rs587781781)

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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 RCV000130031 SCV000184857 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-24 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000637351 SCV000758805 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 735 of the BRCA1 protein (p.Leu735Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine 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 BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 141481). 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 tolerated, 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.
Color RCV000130031 SCV000912041 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001199912 SCV001370679 uncertain significance not specified 2020-05-18 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2203C>G (p.Leu735Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250714 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.2203C>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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