Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000570099 | SCV000663802 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-03-07 | criteria provided, single submitter | clinical testing | The c.146-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 2 in the RAD51C 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; 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 likely pathogenic. |
| Fulgent Genetics, |
RCV002491123 | SCV002802397 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O | 2022-05-18 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002526801 | SCV003197837 | uncertain significance | Fanconi anemia complementation group O | 2022-07-11 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 480520). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (Invitae). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 1 of the RAD51C gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RAD51C are known to be pathogenic (PMID: 20400964, 21990120, 24800917). |