Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000569777 | SCV000665846 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-09-04 | criteria provided, single submitter | clinical testing | The c.4987-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 15 of the BRCA1 gene. 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 Oct;562:217-222). 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; however, direct evidence is insufficient at this time (Ambry internal data). 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 a disease-causing mutation. |
| Labcorp Genetics |
RCV001383012 | SCV001582017 | pathogenic | Hereditary breast ovarian cancer syndrome | 2020-01-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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 this variant disrupts mRNA splicing (PMID: 30209399). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 481445). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 15 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
| Brotman Baty Institute, |
RCV001072943 | SCV001238412 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |