Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001951165 | SCV002241330 | pathogenic | Ataxia-telangiectasia syndrome | 2021-07-08 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 14695534). This sequence change affects an acceptor splice site in intron 27 of the ATM 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 ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (ExAC no frequency). Studies have shown that disruption of this splice site alters ATM gene expression (PMID: 14695534). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV004044381 | SCV004931920 | likely pathogenic | Familial cancer of breast | 2024-01-23 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. |
| Ambry Genetics | RCV004044382 | SCV005016768 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-18 | criteria provided, single submitter | clinical testing | The c.4110-2A>G intronic variant results from an A to G substitution two nucleotides before from coding exon 27 in the ATM 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. 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. |