ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2636T>C (p.Ile879Thr) (rs746265230)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235396 SCV000293885 uncertain significance not provided 2016-02-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.2636T>C at the cDNA level, p.Ile879Thr (I879T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ile879Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ile879Thr occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, Stacker 2013). 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 Ile879Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000456860 SCV000547134 uncertain significance Ataxia-telangiectasia syndrome 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 879 of the ATM protein (p.Ile879Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs746265230, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 246364). 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 threonine 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 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.
Ambry Genetics RCV000562612 SCV000667874 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000562612 SCV000911815 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-27 criteria provided, single submitter clinical testing

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