ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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
Ambry Genetics RCV000569181 SCV000665199 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-12 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000569181 SCV000687550 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000459393 SCV001264583 uncertain significance Ataxia-telangiectasia syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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