ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.116G>T (p.Cys39Phe) (rs80357498)

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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 RCV000509711 SCV000607989 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000030974 SCV000324975 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000206829 SCV000259445 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-07-16 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 39 of the BRCA1 protein (p.Cys39Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant has not been published in the literature and is not present in population databases. Clinvar contains an entry for this variant (RCV000030974). While this variant has not been reported in the literature, different missense substitutions at this codon (p.Cys39Arg, p.Cys39Tyr) have been reported to be deleterious (PMID: 9808526, 11320250, 12827452, 19543972, 21725363, 21922593, 21990134, 23161852, 24489791). This indicates that the cysteine residue is important for BRCA1 protein function. 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. In summary, this missense variant affects a functionally important residue and computational algorithms predict that it is a deleterious change. However, these predictions have not been confirmed experimentally nor are they supported by published genetic studies. For these reasons, this change has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000030974 SCV000053565 pathogenic Breast-ovarian cancer, familial 1 2010-12-20 no assertion criteria provided clinical testing

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