ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8495G>T (p.Arg2832Leu) (rs529296539)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493266 SCV000583200 likely pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing The R2832L variant has been published previously in a patient with chronic lymphocytic leukemia (Landau et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R2832L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same codon (R2832C) and in nearby residues (F2827I/C, P2829L, V2830G, F2834L) have been reported in the Human Gene Mutation Database in association with ataxia-telangiectasia (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic.
Invitae RCV000534120 SCV000622825 uncertain significance Ataxia-telangiectasia syndrome 2017-07-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 2832 of the ATM protein (p.Arg2832Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine 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 a ATM-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C35"). A different missense substitution at this codon (p.Arg2832Cys) has been determined to be pathogenic (PMID: 9443866, 10817650, 10873394, 18634022, 12552559). This suggests that the arginine residue is critical for ATM protein function and that other missense substitutions at this position may also be pathogenic. 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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