ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2873A>G (p.Glu958Gly) (rs587778069)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000159703 SCV000215022 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000159703 SCV000682085 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing
GeneDx RCV000766496 SCV000209714 uncertain significance not provided 2018-11-30 criteria provided, single submitter clinical testing This variant is denoted ATM c.2873A>G at the cDNA level, p.Glu958Gly (E958G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). This variant was observed in two individuals with breast and/or ovarian cancer (Singh 2018). ATM Glu958Gly was observed at an allele frequency of 0.07% (22/30780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the region of interaction with beta-adaptin (Tavtigian 2009). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Glu958Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000159703 SCV000821842 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
ITMI RCV000120128 SCV000084266 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000528438 SCV000622371 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 958 of the ATM protein (p.Glu958Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs587778069, ExAC 0.07%). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 133611). 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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