ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1112C>T (p.Thr371Ile) (rs879254289)

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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 RCV000565895 SCV000660607 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000565895 SCV000681954 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing
GeneDx RCV000236757 SCV000294079 uncertain significance not provided 2017-10-12 criteria provided, single submitter clinical testing This variant is denoted ATM c.1112C>T at the cDNA level, p.Thr371Ile (T371I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr371Ile was not observed in large population cohorts (Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Thr371Ile 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 Thr371Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000460140 SCV000546805 uncertain significance Ataxia-telangiectasia syndrome 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 371 of the ATM protein (p.Thr371Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 246498). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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