ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6671T>C (p.Met2224Thr) (rs730881313)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159643 SCV000209632 uncertain significance not provided 2014-10-01 criteria provided, single submitter clinical testing This variant is denoted ATM c.6671T>C at the cDNA level, p.Met2224Thr (M2224T) 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 Met2224Thr 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 Met2224Thr occurs at a position that is well conserved across species and is located within the FAT domain (Tavtigian 2009, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Met2224Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000693596 SCV000821471 uncertain significance Ataxia-telangiectasia syndrome 2018-01-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 2224 of the ATM protein (p.Met2224Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs730881313, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181884). 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.

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