ClinVar Miner

Submissions for variant NM_001330368.2(C11orf65):c.640+20528_640+20538del (rs587782847)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132441 SCV000187535 pathogenic Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Deficient protein function in appropriate functional assay(s);Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence
Color RCV000132441 SCV000687876 pathogenic Hereditary cancer-predisposing syndrome 2020-05-14 criteria provided, single submitter clinical testing
Invitae RCV001211331 SCV001382867 likely pathogenic Ataxia-telangiectasia syndrome 2019-09-27 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the ATM gene (p.Lys3016Serfs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acids of the ATM protein and extend the protein by an additional 1 amino acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 142954). 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, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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