ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2887A>G (p.Met963Val) (rs374353016)

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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 RCV000132462 SCV000187556 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000132462 SCV000903008 likely benign Hereditary cancer-predisposing syndrome 2015-09-22 criteria provided, single submitter clinical testing
GeneDx RCV000236226 SCV000292902 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.2887A>G at the cDNA level, p.Met963Val (M963V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been observed in at least one individual with advanced cancer (Mandelker 2017). ATM Met963Val was observed at an allele frequency of 0.042% (10/24,032) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the region of interaction with beta-adaptin (Tavtigian 2009). 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 Met963Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168295 SCV000218973 uncertain significance Ataxia-telangiectasia syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 963 of the ATM protein (p.Met963Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs374353016, ExAC 0.04%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142966). 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 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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