Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000539798 | SCV000628287 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-19 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the ATPase-C domain, which is important for RAD50 ATPase activity (PMID: 10892749, 24894818). While functional studies have not been performed to directly test the effect of this variant on RAD50 protein function, this suggests that disruption of this region of the protein is causative of disease. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 25 and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 457468). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 24 of the RAD50 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. |
| Ambry Genetics | RCV000539798 | SCV001182619 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-07-13 | criteria provided, single submitter | clinical testing | The c.3753-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 25 of the RAD50 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this alteration is classified as likely pathogenic. |
| Baylor Genetics | RCV003459187 | SCV004207451 | likely pathogenic | Nijmegen breakage syndrome-like disorder | 2022-02-28 | criteria provided, single submitter | clinical testing |