ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8530A>G (p.Ile2844Val) (rs756230327)

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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 RCV000167366 SCV000218218 likely benign Hereditary cancer-predisposing syndrome 2018-05-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Integrated Genetics/Laboratory Corporation of America RCV000779779 SCV000916569 uncertain significance not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: ATM c.8530A>G (p.Ile2844Val) results in a conservative amino acid change located in the catalytic domain of the Phosphatidylinositol 3-/4-kinase (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246018 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.1e-06 vs 4.003-03), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4545C>T in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000473223 SCV000547010 uncertain significance Ataxia-telangiectasia syndrome 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2844 of the ATM protein (p.Ile2844Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs756230327, ExAC 0.01%) but has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 187621). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant has uncertain impact on ATM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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