ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5945A>G (p.Gln1982Arg) (rs543980602)

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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 RCV000130454 SCV000185319 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
Color RCV000130454 SCV000682291 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing
GeneDx RCV000522109 SCV000617915 uncertain significance not provided 2018-04-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.5945A>G at the cDNA level, p.Gln1982Arg (Q1982R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant was absent in 4112 breast cases but was present in 1/2399 controls in a large meta-analysis of case-control studies (Tavtigian 2009). ATM Gln1982Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Gln1982Arg is located in the FAT domain (Stracker 2013). 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 Gln1982Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000203883 SCV000260129 uncertain significance Ataxia-telangiectasia syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 1982 of the ATM protein (p.Gln1982Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs543980602, ExAC 0.02%). This variant has been reported in one control individual in a breast cancer study (PMID: 19781682). This variant has not been reported in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141800). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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