ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2531G>A (p.Gly844Glu) (rs587781808)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130079 SCV000184906 likely benign Hereditary cancer-predisposing syndrome 2018-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000130079 SCV000911592 likely benign Hereditary cancer-predisposing syndrome 2017-04-07 criteria provided, single submitter clinical testing
Counsyl RCV000168121 SCV000792870 uncertain significance Ataxia-telangiectasia syndrome 2017-07-19 criteria provided, single submitter clinical testing
GeneDx RCV000211983 SCV000209708 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted ATM c.2531G>A at the cDNA level, p.Gly844Glu (G844E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant was observed in at least two individuals with breast cancer (Hauke 2018). ATM Gly844Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether ATM Gly844Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000168121 SCV000218778 uncertain significance Ataxia-telangiectasia syndrome 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 844 of the ATM protein (p.Gly844Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs587781808, ExAC 0.003%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141514). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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