ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2446_2447delGCinsCT (p.Ala816Leu) (rs587781956)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130332 SCV000185182 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
Color RCV000130332 SCV000902989 likely benign Hereditary cancer-predisposing syndrome 2016-04-19 criteria provided, single submitter clinical testing
GeneDx RCV000481791 SCV000571834 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing This variant is denoted ATM c.2446_2447delGCinsCT at the cDNA level and p.Ala816Leu (A816L) at the protein level. The normal sequence, with the bases that are deleted and inserted in brackets, is CATT[delGC][insCT]AGAT. This in-frame deletion and insertion results in the missense change of an Alanine to a Leucine (GCA>CTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ala816Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Ala816Leu is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Ala816Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000688351 SCV000815957 uncertain significance Ataxia-telangiectasia syndrome 2018-06-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with leucine at codon 816 of the ATM protein (p.Ala816Leu). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and leucine. 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 disease. ClinVar contains an entry for this variant (Variation ID: 141714). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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