ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.754del (p.Arg252fs) (rs1555593195)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588472 SCV000699300 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-16 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.754delC (p.Arg252Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.783T>G [p.Tyr261X], c.784delC [p.Gln262fs). The variant has been identified in at least two patients with triple-negative breast cancer (Lang_BRCA1&2_IJC_2017; Yang_PLoS One_2015) and is absent from the large control database ExAC and control cohorts reported in the literature (0/122396 control chromosomes). One in silico tool predicts a damaging outcome for this variant. Taken together, this variant is classified as pathogenic.
Invitae RCV000588472 SCV000758912 pathogenic Hereditary breast and ovarian cancer syndrome 2017-09-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg252Valfs*46) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hereditary breast and ovarian cancer syndrome (PMID: 25927356). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.

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