ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4082A>G (p.Gln1361Arg) (rs141921797)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164614 SCV000215277 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000164614 SCV000682183 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing
GeneDx RCV000479421 SCV000564637 uncertain significance not provided 2018-12-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.4082A>G at the cDNA level, p.Gln1361Arg (Q1361R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant was observed in individuals with colon cancer and kidney cancer (Yehia 2018). ATM Gln1361Arg was observed at an allele frequency of 0.06% (15/24,028) in individuals of African ancestry in large population cohorts (Lek 2016). This variant 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 Gln1361Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780899 SCV000918535 uncertain significance not specified 2018-10-19 criteria provided, single submitter clinical testing Variant summary: ATM c.4082A>G (p.Gln1361Arg) results in a conservative amino acid change located in the armadillo-type fold (IPR016024) 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 6.6e-05 in 120724 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4082A>G has been reported in the literature in individuals with no clinical information (Haiman 2013). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000167992 SCV000218642 uncertain significance Ataxia-telangiectasia syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 1361 of the ATM protein (p.Gln1361Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs141921797, ExAC 0.07%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 185234). 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: "Benign"; 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.
Mendelics RCV000167992 SCV000838533 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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