ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2771G>A (p.Arg924Gln) (rs587782298)

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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 RCV000131181 SCV000186128 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000465123 SCV000547012 uncertain significance Ataxia-telangiectasia syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 924 of the ATM protein (p.Arg924Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587782298, ExAC 0.06%). This variant has been reported in an individual affected with breast cancer (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 142194). 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.
GeneDx RCV000483446 SCV000564621 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.2771G>A at the cDNA level, p.Arg924Gln (R924Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant was observed in 1/4112 breast cancer cases and 0/2399 controls in a large meta-analysis (Tavtigian 2009). ATM Arg924Gln was observed at an allele frequency of 0.04% (12/30782) in individuals of South Asian ancestry 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 Arg924Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131181 SCV000682076 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing

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