ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7559T>G (p.Met2520Arg) (rs587782692)

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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 RCV000132126 SCV000187194 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000522314 SCV000617132 uncertain significance not provided 2017-08-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.7559T>G at the cDNA level, p.Met2520Arg (M2520R) at the protein level, and results in the change of a Methionine to an Arginine (ATG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Met2520Arg was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Methionine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Met2520Arg occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013). Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function. In addition, multiple splicing models predict that this variant may create a cryptic splice acceptor site downstream of the natural splice acceptor site and possibly lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether ATM Met2520Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000627852 SCV000748736 uncertain significance Ataxia-telangiectasia syndrome 2018-03-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 2520 of the ATM protein (p.Met2520Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is present in population databases (rs587782692, ExAC 0.002%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142749). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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