ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5107T>C (p.Tyr1703His) (rs863224763)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197224 SCV000254993 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-05-14 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 1703 of the BRCA1 protein (p.Tyr1703His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant has not been reported in affected individuals in the literature, and is not present in population databases. This variant has also not been reported in affected patients in the Breast Cancer Information Core database (PMID: 10923033) and the Universal Mutation Database (PMID: 22144684). A different amino acid substitution at this codon (c.5108A>C, p.Tyr1703Ser) has been reported in an individual suspected of having breast and/or ovarian cancer. Functional analysis of this missense change shows that it abolishes the transcriptional activity of BRCA1 (PMID: 23613828). However, the clinical significance of this finding is uncertain and does not contribute to the classification of the p.Tyr1703His change. In summary, this is a novel missense change that may impact protein function and cause disease. However, since there is insufficient evidence at this time to prove that conclusively, it has been classified as a Variant of Uncertain Significance. 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. Also, experimental studies have shown that this missense change disrupts the transcriptional transactivation activity of the BRCA1 protein (PMID: 10811118).
Brotman Baty Institute,University of Washington RCV001078063 SCV001244101 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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