ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6536T>C (p.Ile2179Thr) (rs878853532)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229363 SCV000283019 uncertain significance Ataxia-telangiectasia syndrome 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2179 of the ATM protein (p.Ile2179Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. 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: 236754). 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 disruptive, 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.
GeneDx RCV000255846 SCV000322059 uncertain significance not provided 2018-08-15 criteria provided, single submitter clinical testing This variant is denoted ATM c.6536T>C at the cDNA level, p.Ile2179Thr (I2179T) 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 a pathogenic or benign germline variant. ATM Ile2179Thr 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM Ile2179Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572519 SCV000660714 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000572519 SCV000682346 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779807 SCV000916612 uncertain significance not specified 2018-12-20 criteria provided, single submitter clinical testing Variant summary: ATM c.6536T>C (p.Ile2179Thr) results in a non-conservative amino acid change located in the PIK-related kinase domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246228 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6536T>C in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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