Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000580882 | SCV000683294 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-12-14 | criteria provided, single submitter | clinical testing | This variant causes an A>T nucleotide substitution at the -2 position of intron 20 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional study reported this variant as defective in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in at least one individual with triple-negative breast cancer (PMID: 30350268) and additional individuals considered at-risk for breast and/or ovarian cancer (PMID: 22798144, 29673794). 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. Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Ambry Genetics | RCV000580882 | SCV003911973 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-17 | criteria provided, single submitter | clinical testing | The c.5333-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 20 in the BRCA1 gene. This alteration has been reported in several Korean breast cancer cohorts (Kim H et al. Breast Cancer Res Treat, 2012 Aug;134:1315-26; Kim DH et al. BMC Med Genet, 2017 Mar;18:38) and in 1 of 999 Korean triple negative breast cancer patients undergoing BRCA1/2 genetic testing (Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395). This variant was also reported in 1/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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). In addition to the data presented in the literature, 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. |
| Baylor Genetics | RCV000077616 | SCV004217011 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2021-12-22 | criteria provided, single submitter | clinical testing | |
| Sharing Clinical Reports Project |
RCV000077616 | SCV000109419 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2010-11-30 | no assertion criteria provided | clinical testing | |
| Brotman Baty Institute, |
RCV000077616 | SCV001243129 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |