ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8633-2A>C

dbSNP: rs81002886
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001381420 SCV001579803 pathogenic Hereditary breast ovarian cancer syndrome 2022-11-18 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in an insertion from intron 20 and a partial deletion of exon 21 and introduces a premature termination codon (PMID: 16619214). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 1069528). Disruption of this splice site has been observed in individual(s) with ovarian cancer (PMID: 16619214). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 20 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Ambry Genetics RCV004951656 SCV005548607 likely pathogenic Hereditary cancer-predisposing syndrome 2024-07-03 criteria provided, single submitter clinical testing The c.8633-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 20 in the BRCA2 gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

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