ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2150G>A (p.Arg717Gln) (rs768874297)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573560 SCV000668042 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000573560 SCV000913556 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-23 criteria provided, single submitter clinical testing
GeneDx RCV000485077 SCV000568987 uncertain significance not provided 2018-03-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.2150G>A at the cDNA level, p.Arg717Gln (R717Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has been observed in at least one individual with a personal and family history of breast cancer (Mannan 2016). ATM Arg717Gln 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 evidence, it is unclear whether ATM Arg717Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000628158 SCV000749051 uncertain significance Ataxia-telangiectasia syndrome 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 717 of the ATM protein (p.Arg717Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs768874297, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 26911350). ClinVar contains an entry for this variant (Variation ID: 420250). 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 glutamine 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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