ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.713T>C (p.Ile238Thr) (rs149116878)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480166 SCV000566051 uncertain significance not provided 2015-03-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.713T>C at the cDNA level, p.Ile238Thr (I238T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ile238Thr was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ile238Thr occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Ile238Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574196 SCV000665569 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000574196 SCV001358186 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-05 criteria provided, single submitter clinical testing
Invitae RCV001222216 SCV001394307 uncertain significance Ataxia-telangiectasia syndrome 2019-07-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 238 of the ATM protein (p.Ile238Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs149116878, ExAC 0.01%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 418756). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25". 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.

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