ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5067G>A (p.Met1689Ile) (rs1597825629)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000798297 SCV000937904 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 1689 of the BRCA1 protein (p.Met1689Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Met1689 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been observed in individuals with BRCA1-related disease (PMID: 15172985, 18703817, 20516115, 21990134, 27272900), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Brotman Baty Institute,University of Washington RCV001076311 SCV001242034 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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