ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8845G>A (p.Val2949Ile) (rs587782497)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131626 SCV000186648 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000485678 SCV000571958 uncertain significance not provided 2018-02-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.8845G>A at the cDNA level, p.Val2949Ile (V2949I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant was reported in an individual with splenic marginal zone lymphoma, although germline versus somatic status is unclear (Parry 2015). ATM Val2949Ile was not observed in large population cohorts (Lek 2016). This variant is located in the kinase 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 Val2949Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000695433 SCV000823931 uncertain significance Ataxia-telangiectasia syndrome 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2949 of the ATM protein (p.Val2949Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142487). 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 disruptive, 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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