ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8965C>G (p.Gln2989Glu) (rs147695170)

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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 RCV000129371 SCV000184135 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129371 SCV000682529 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-18 criteria provided, single submitter clinical testing
GeneDx RCV000212094 SCV000209669 uncertain significance not provided 2018-05-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.8965C>G at the cDNA level, p.Gln2989Glu (Q2989E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). This variant has been observed in at least one individual with a personal history of a Lynch syndrome-associated cancer and/or polyps, who also carried a pathogenic MSH2 variant (Yurgelun 2015). ATM Gln2989Glu was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located within the FATC domain (Stracker 2013). 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 Gln2989Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204504 SCV000260823 uncertain significance Ataxia-telangiectasia syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 2989 of the ATM protein (p.Gln2989Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs147695170, ExAC 0.001%). This variant was reported in an individual with suspected Lynch syndrome, who also carried a pathogenic MSH2 variant (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 141036). 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. 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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