ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4396C>G (p.Arg1466Gly) (rs730881369)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212014 SCV000209735 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing This variant is denoted ATM c.4396C>G at the cDNA level, p.Arg1466Gly (R1466G) at the protein level, and results in the change of an Arginine to a Glycine (CGA>GGA). This variant has been observed in at least two individuals with breast cancer and one healthy control (Tung 2015, Decker 2017, Tiao 2017). ATM Arg1466Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Arg1466Gly is not located within 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 Arg1466Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159723 SCV000215787 likely benign Hereditary cancer-predisposing syndrome 2020-07-16 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Invitae RCV000197917 SCV000254106 uncertain significance Ataxia-telangiectasia syndrome 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1466 of the ATM protein (p.Arg1466Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs730881369, ExAC 0.002%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181956). 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. 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.
Color Health, Inc RCV000159723 SCV000682202 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-01 criteria provided, single submitter clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000159723 SCV001911461 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.4396C>G (p.Arg1466Gly) variant appears only twice in the gnomAD v2.1.1 non-cancer dataset (0.0007% frequency), specifically in the European (non-Finnish) subpopulation (PM2; This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice – GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and VEST4 (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PP3 (PMID: 33280026).

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