Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001015625 | SCV001176475 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-30 | criteria provided, single submitter | clinical testing | The c.2466+1552G>C intronic variant results from a G to C substitution 1552 nucleotides after coding exon 15 in the ATM gene. This variant has been shown to activate a cryptic splice acceptor site that results in the insertion of 95 nucleotides between coding exon 15 and coding exon 16, leading to a premature stop codon that is expected to trigger nonsense-mediated mRNA decay (Moles-Fernández A et al. Cancers (Basel), 2021 Jul 3;13(13):3341). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant has been detected in conjunction with a pathogenic mutation in ATM in an individual without clinical features of ataxia-telangiectasia, suggesting that this variant may be hypomorphic (Ambry internal data). As risk estimates are unknown at this time, clinical correlation is advised. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV002549424 | SCV002991797 | pathogenic | Ataxia-telangiectasia syndrome | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 16 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of hereditary cancer (PMID: 36008414). ClinVar contains an entry for this variant (Variation ID: 821324). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |