ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.9050_9051insTTCA (p.Lys3018fs) (rs1555151854)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000558630 SCV000622881 likely pathogenic Ataxia-telangiectasia syndrome 2017-02-28 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotide in exon 63 of the ATM mRNA (c.9050_9051insTTCA), causing a frameshift at codon 3018. This creates a premature translational stop signal in the last exon of the ATM mRNA (p.Lys3018Serfs*46). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acids of the ATM protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. This frameshift variant is expected to disrupt the C-terminal FATC domain (residues 2963-3056 or 3024-3056) of the ATM protein, which is required for binding to TIP60 for signaling activation (PMID: 23532176, 19781682, 18813293). A downstream truncating variant (p.Arg3047*) affecting the same region has been determined to be pathogenic (PMID: 8755918, 19691550, 18560558, 10980530, 26628246). This suggests that disruption of this region of the ATM protein is causative of disease. In summary, this variant is a novel frameshift variant that is expected to disrupt the region being proven to be causative of disease. 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.

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