ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.185_190del (p.Pro62_Cys64delinsArg) (rs1555597224)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000557230 SCV000635816 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-04-09 criteria provided, single submitter clinical testing This sequence change deletes 6 nucleotides from exon 4 of the BRCA1 mRNA (c.185_190delCTTTAT). This leads to the deletion of 2 amino acid residues and the insertion of one amino acid residue in the BRCA1 protein (p.Pro62_Cys64delinsArg), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. Experimental studies and prediction algorithms are not available for this variant. However, this variant affects the highly conserved Cys64 residue within the N-terminal RING domain of the BRCA1 protein (PMID: 22843421, 20029420). Three missense substitutions at this codon (p.Cys64Arg, p.Cys64Tyr, p.Cys64Gly) have been determined to be pathogenic (PMID: 24516540, 26246475, 11320250, 15131401, 7894491, 23867111). This suggests that the cysteine residue is critical for BRCA1 protein function and that other alterations of this residue may also be pathogenic. In summary, this is a novel variant with uncertain impact on protein function. While it affects a residue that has been shown to be important for protein function, without additional genetic or functional data it has been classified as a Variant of Uncertain Significance.

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