ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8314G>A (p.Gly2772Arg) (rs1064794239)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486226 SCV000568337 uncertain significance not provided 2018-06-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.8314G>A at the cDNA level, p.Gly2772Arg (G2772R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has been observed in at least two individuals with breast cancer and in one healthy control subject (Dork 2001, Tavtigian 2009, Hauke 2018, Podralska 2018). ATM Gly2772Arg was associated with cell viability, sensitivity to ionizing radiation, and induction of ATM kinase activity similar to wild type in both in vitro and in vivo assays in ataxia-telangiectasia and normal control lymphoblastoid cell lines (Scott 2002). ATM Gly2772Arg was not observed in large population cohorts (Lek 2016). This variant is located in the kinase domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Gly2772Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000565973 SCV000660644 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000670258 SCV000795091 uncertain significance Ataxia-telangiectasia syndrome 2017-10-26 criteria provided, single submitter clinical testing
Invitae RCV000670258 SCV000952280 uncertain significance Ataxia-telangiectasia syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2772 of the ATM protein (p.Gly2772Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast cancer (PMID: 11606401, 19781682, 29678143). However, the variant was also identified in a control cohort (PMID: 29678143). ClinVar contains an entry for this variant (Variation ID: 420015). Experimental studies have shown that this missense change does not affect ATM stability, kinase activity or ability to induce a response to irradiation (PMID: 11805335, 15279808). 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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