Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000688168 | SCV000815770 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2023-06-14 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 13 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with or undergoing testing for hereditary breast and/or ovarian cancer (PMID: 26622941, 29446198, 30078507). ClinVar contains an entry for this variant (Variation ID: 567954). Studies have shown that disruption of this splice site results in activation of cryptic splice site and introduces a premature termination codon (PMID: 26622941). 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. |
| Color Diagnostics, |
RCV001191823 | SCV001359734 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-08 | criteria provided, single submitter | clinical testing | This variant causes an A to C nucleotide substitution at the -2 position of intron 13 of the BRCA1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, two different canonical splice site variants at this acceptor site, c.4485-1G>A and c.4485-1G>T, have been shown to cause out-of-frame splicing in RNA analysis of tumor- and carrier-derived RNA (PMID: 26622941, 31843900). This variant has been detected in at least four individuals affected with ovarian or breast cancer (PMID: 30078507, 31825140, 32850417, 34254208). Other canonical splice site variants at this splice acceptor site have been reported as disease-causing in ClinVar (variation ID: 55213, 55214, 246501, 267551, 433715) and detected in individuals affected with breast or ovarian cancer (PMID: 9333265, 11595708, 12181777, 12960223, 24249303, 27553291, 28179634, 29446198, 30287823, 31528241, 33471991; Leiden Open Variation Database DB-ID BRCA1_004959). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001283905 | SCV001469391 | likely pathogenic | not provided | 2019-11-14 | criteria provided, single submitter | clinical testing | The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality. |
| Fulgent Genetics, |
RCV005021054 | SCV005647131 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S | 2024-04-24 | criteria provided, single submitter | clinical testing |