Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000557078 | SCV000622219 | likely pathogenic | Ataxia-telangiectasia syndrome | 2017-03-24 | criteria provided, single submitter | clinical testing | This variant is an in-frame deletion of the genomic region encompassing exon 5 of the ATM gene. It preserves the integrity of the reading frame. Deletions of exon 5 have not been reported in the literature in individuals with an ATM-related disease. While this variant is not anticipated to result in nonsense mediated decay, it is expected to delete 55 amino acids from the ATM protein (p.Arg111_Glu166delinsLys). An experimental study has shown that the deletion of amino acid residues 110-130 disrupts the interaction between the ATM and TP53 proteins, and the ability of ATM to rescue the hypersensitivity to ionizing radiation in ATM-deficient cells (PMID: 15713674). Pathogenic sequence changes within the acceptor splice site (c.332-1G>A) and donor splice site (c.496+5G>A) of exon 5 have been reported in individuals affected with ataxia-telangiectasia (PMID: 10980530, 15054841, 19535770). An experimental study using RNA derived from an affected individual has shown that the c.496+5G>A variant results in the in-frame skipping of exon 5 (PMID: 15054841). These results suggest that exon 5 is important for normal ATM functioning. In summary, this variant is a novel deletion that removes a single, in-frame exon of the ATM protein, which has been shown to contain an important protein functional domain. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |