ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1670T>C (p.Met557Thr) (rs786202770)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165751 SCV000216495 uncertain significance Hereditary cancer-predisposing syndrome 2014-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000486174 SCV000564613 uncertain significance not provided 2015-02-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.1670T>C at the cDNA level, p.Met557Thr (M557T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Met557Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Met557Thr occurs at a position that is poorly conserved across species, with Threonine being the naturally occurring amino acid at this position in several species, and is not located in a known functional domain (Tavtigian 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Met557Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000556946 SCV000622276 uncertain significance Ataxia-telangiectasia syndrome 2017-04-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 557 of the ATM protein (p.Met557Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186202). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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