ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6680G>A (p.Arg2227His) (rs879254132)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563259 SCV000660552 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position,Insufficient or conflicting evidence
Color RCV000563259 SCV000905074 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing
GeneDx RCV000235577 SCV000293602 uncertain significance not provided 2017-10-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.6680G>A at the cDNA level, p.Arg2227His (R2227H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg2227His was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. ATM Arg2227His occurs at a position that is conserved across species and is located in the FAT domain (Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Arg2227His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000527070 SCV000622684 uncertain significance Ataxia-telangiectasia syndrome 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2227 of the ATM protein (p.Arg2227His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. 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: 246165). 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. A different missense substitution at this codon (p.Arg2227Cys) has been determined to be pathogenic (PMID: 12552559, 15843990, 16380133, 19691550, 23264026, 23640770, 18504682, 22213089). This suggests that the arginine residue is critical for ATM protein function and that other missense substitutions at this position may also be pathogenic. 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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