ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1249A>G (p.Thr417Ala) (rs863224556)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000200842 SCV000254056 uncertain significance Ataxia-telangiectasia syndrome 2016-12-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 417 of the ATM protein (p.Thr417Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 216191). 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 alanine 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 is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000217576 SCV000275102 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-06 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000480273 SCV000569881 uncertain significance not provided 2018-06-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.1249A>G at the cDNA level, p.Thr417Ala (T417A) at the protein level, and results in the change of a Threonine to an Alanine (ACC>GCC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Thr417Ala was not observed in large population cohorts (Lek 2016). ATM Thr417Ala 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 Thr417Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000217576 SCV000906595 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780896 SCV000918531 uncertain significance not specified 2017-12-26 criteria provided, single submitter clinical testing Variant summary: The ATM c.1249A>G (p.Thr417Ala) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 2/3 in silico tools (SNPsandGO and Mutation taster not captured due to low reliability index). This variant is absent in 271418 control chromosomes (gnomAD). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. An internal sample carrying this variant also carries a variant of unknown significance p.V2705I in the same gene. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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