Submissions for variant NM_000051.4(ATM):c.4396C>G (p.Arg1466Gly)

gnomAD frequency: 0.00003  dbSNP: rs730881369

Total submissions: 6

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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000197917	SCV000254106	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1466 of the ATM protein (p.Arg1466Gly). This variant is present in population databases (rs730881369, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 181956). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 Diagnostics, LLC DBA Color Health	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; http://gnomad.broadinstitute.org). 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).
Baylor Genetics	RCV003467230	SCV004209413	uncertain significance	Familial cancer of breast	2023-09-21	criteria provided, single submitter	clinical testing