ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4465C>T (p.Arg1489Cys) (rs754181173)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569181 SCV000665199 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000569181 SCV000687550 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing
GeneDx RCV000766502 SCV000564641 uncertain significance not provided 2018-07-03 criteria provided, single submitter clinical testing This variant is denoted ATM c.4465C>T at the cDNA level, p.Arg1489Cys (R1489C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Arg1489Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg1489Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000483688 SCV000593503 uncertain significance not specified 2016-10-12 criteria provided, single submitter clinical testing
Invitae RCV000459393 SCV000546828 uncertain significance Ataxia-telangiectasia syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1489 of the ATM protein (p.Arg1489Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs754181173, ExAC 0.003%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 407548). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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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