Submissions for variant NM_000051.4(ATM):c.6828_6829insTTTTTTTTTTTTTTTTTTNNNNNNNNNNCATGTGGAATTTGTGCAGGTTAGTTAAATATGTATACATGTGCCATGATGGTCCGCTGCACACACTAATGTTTCATCTAGACATAGGTATATCTCGAAAGGGCAATATTT (p.Gln2277delinsPhePhePhePhePhePheXaaXaaXaaXaaCysGlyIleCysAlaGlyTer)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003500491	SCV004337132	pathogenic	Ataxia-telangiectasia syndrome	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 47 of the ATM gene (c.6828_6829ins?). The exact size and sequence of the insertion cannot be determined by the current assay. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. Studies have shown that this variant results in skipping of Exon 47, but is expected to preserve the integrity of the reading-frame (Invitae). This variant disrupts the FAT domain, which is necessary for ATM dimerization (PMID: 23532176, 35008949). While functional studies have not been performed to directly test the effect of this variant on ATM protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.