ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5056C>T (p.His1686Tyr) (rs1555579648)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000765358 SCV000896623 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000637812 SCV000759291 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-09-02 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 1686 of the BRCA1 protein (p.His1686Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. 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 (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 and their clinical significance is uncertain. Different missense substitutions at this codon (p.His1686Arg and p.His1686Gln) have been determined to be pathogenic (PMID: 25452441, 23867111, 18757339, 12496477). This suggests that the histidine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. 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.

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