ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6814G>A (p.Glu2272Lys) (rs886039471)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565662 SCV000660521 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
Counsyl RCV000553239 SCV000793244 uncertain significance Ataxia-telangiectasia syndrome 2017-08-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000586472 SCV000708587 uncertain significance not provided 2017-05-12 criteria provided, single submitter clinical testing
GeneDx RCV000586472 SCV000322063 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.6814G>A at the cDNA level, p.Glu2272Lys (E2272K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in an individual with childhood acute lymphoblastic leukemia (Gumy Pause 2003). ATM Glu2272Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Glu2272Lys is located in the FAT 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 information, it is unclear whether ATM Glu2272Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586472 SCV000694332 uncertain significance not provided 2016-06-20 criteria provided, single submitter clinical testing Variant summary: The ATM c.6814G>A (p.Glu2272Lys) variant involves the alteration of a conserved nucleotide. The variant is present in RAD-3 domain however it is unknown whether the domain is critical to protein function or it involves a critical residue. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 120880 control chromosomes. The variant was found as germline variant in one acute lymphoblastic leukemia sample and as somatic variant in one esophagus sample (Gumy Pause_2003, Lin_2014); however without strong evidence for causality. Because of the absence of sufficient clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000553239 SCV000622689 uncertain significance Ataxia-telangiectasia syndrome 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2272 of the ATM protein (p.Glu2272Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with B-precursor acute lymphoblastic leukemia (PMID: 12673804). ClinVar contains an entry for this variant (Variation ID: 265315). 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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