ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1379C>T (p.Thr460Met) (rs587781841)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130139 SCV000184973 uncertain significance Hereditary cancer-predisposing syndrome 2015-01-07 criteria provided, single submitter clinical testing
Invitae RCV000466948 SCV000546849 uncertain significance Ataxia-telangiectasia syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 460 of the ATM protein (p.Thr460Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141561). 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 methionine 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.
GeneDx RCV000478287 SCV000565853 uncertain significance not provided 2017-07-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.1379C>T at the cDNA level, p.Thr460Met (T460M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr460Met was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr460Met occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Thr460Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
PreventionGenetics,PreventionGenetics RCV000478287 SCV000805496 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing
Color RCV000130139 SCV000913545 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing

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