ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.518G>T (p.Arg173Met) (rs372694758)

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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 RCV000575164 SCV000667842 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000575164 SCV000913530 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing
GeneDx RCV000159673 SCV000209674 uncertain significance not specified 2017-03-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.518G>T at the cDNA level, p.Arg173Met (R173M) at the protein level, and results in the change of an Arginine to a Methionine (AGG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Arg173Met was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg173Met occurs at a position that is not conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Arg173Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000456186 SCV000547157 uncertain significance Ataxia-telangiectasia syndrome 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with methionine at codon 173 of the ATM protein (p.Arg173Met). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and methionine. 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: 181909). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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