ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1234T>C (p.Trp412Arg) (rs587779812)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211958 SCV000149046 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.1234T>C at the cDNA level, p.Trp412Arg (W412R) at the protein level, and results in the change of a Tryptophan to an Arginine (TGG>CGG). This variant has been associated with reduced protein expression, but with some retained irradiation-induced kinase activity, the clinical significance of which is unclear (Taylor 2015). ATM Trp412Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Tryptophan and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Trp412Arg occurs at a position that is conserved across species and is not located within a known functional domain. While protein-based in silico analyses predict that this variant is probably damaging to protein structure and function, splicing models are uninformative; therefore, 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 Trp412Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115137 SCV000216232 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000206069 SCV000261145 uncertain significance Ataxia-telangiectasia syndrome 2018-06-20 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 412 of the ATM protein (p.Trp412Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127333). Experimental studies have shown that this missense change reduces ATM expression and irradiation-induced phosphorylation ability (PMID: 25040471). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.