ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4186-2A>G (rs878854950)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231953 SCV000289794 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-14 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 240799). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Experimental studies have shown that variants at this splice site disrupt the consensus splice site and strengthen a cryptic acceptor site in exon 12 (also known as exon 13 in the literature), located 3 nucleotides downstream of the natural splice site. This results in an in-frame deletion of 1 amino acid (p.Gln1396del), but otherwise preserves the integrity of the reading frame (PMID: 24569164). These studies suggest that the clinical significance of this splice variant may be uncertain. 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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