ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6194T>C (p.Ile2065Thr) (rs372838622)

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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 RCV000219142 SCV000274086 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000219142 SCV000911229 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-28 criteria provided, single submitter clinical testing
GeneDx RCV000235342 SCV000293095 uncertain significance not provided 2018-05-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.6194T>C at the cDNA level, p.Ile2065Thr (I2065T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ile2065Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 Ile2065Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000234193 SCV000283009 uncertain significance Ataxia-telangiectasia syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2065 of the ATM protein (p.Ile2065Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs372838622, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 230510). 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 C25"). 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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