Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000048727 | SCV000076740 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2024-05-01 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 21638052, 29907814). ClinVar contains an entry for this variant (Variation ID: 55346). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 16 (also known as exon 17) and introduces a premature termination codon (PMID: 21638052, 22113256). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV000129699 | SCV000184500 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-11-27 | criteria provided, single submitter | clinical testing | The c.4987-3C>G intronic pathogenic mutation results from a C to G substitution 3 nucleotides upstream from coding exon 15 in the BRCA1 gene. 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. Multiple different RNA studies have found that this variant produces a substantial amount of aberrant, frameshifting transcript (Ambry internal data; Brandão RD et al. Breast Cancer Res Treat, 2011 Oct;129:971-82; Brandão RD et al. Breast Cancer Res Treat, 2012 Jan;131:723-5). One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Other alterations impacting the same acceptor site (c.4987A>T, c.4987-1G>A, c.4987-5T>A) have been shown to have a similar impact on splicing (Bonnet C et al. J Med Genet, 2008 Jul;45:438-46; Colombo M et al. PLoS One, 2013 Feb;8:e57173; Ahlborn LB et al. Breast Cancer Res Treat, 2015 Apr;150:289-98). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |
| Brotman Baty Institute, |
RCV001077889 | SCV001243892 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |