Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000792146 | SCV000931424 | pathogenic | Ataxia-telangiectasia syndrome | 2019-10-01 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 57-63 of the ATM gene. The 5' boundary is likely confined to intron 56. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. Deletions of exons 57-63 have been reported in a suspected hereditary breast and ovarian cancer family (PMID: 27581129), and individuals affected with astrocytoma, glioblastoma, and colon polyps (PMID: 26681312). This deletion eliminates a portion of the kinase domain (encoded by exons 55-62) and the entire FATC domain (encoded by exon 63) of the ATM protein. Both domains are known to be required for normal ATM protein function (PMID: 23532176). In addition, multiple missense substitutions in exons 57-63 have been determined to be pathogenic (PMID: 19781682, 19431188, 10873394,12552566). This suggests that this region is critical for proper ATM kinase function. Loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic. |