ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2149C>T (p.Arg717Trp) (rs147515380)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129107 SCV000183818 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Athena Diagnostics Inc RCV000586332 SCV000840923 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing
Color RCV000129107 SCV000537605 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing
GeneDx RCV000586332 SCV000278814 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.2149C>T at the cDNA level, p.Arg717Trp (R717W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was observed in an individual with a personal history of ovarian cancer, as well as in an individual with an unspecified cancer type (Petereit 2013, Lu 2015). ATM Arg717Trp 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg717Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000129107 SCV000821834 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586332 SCV000694209 uncertain significance not provided 2015-10-30 criteria provided, single submitter clinical testing
Invitae RCV000457240 SCV000546839 uncertain significance Ataxia-telangiectasia syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 717 of the ATM protein (p.Arg717Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs147515380, ExAC 0.01%). This variant has been reported in an individual affected with cancer (PMID: 24416720). ClinVar contains an entry for this variant (Variation ID: 140879). 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. 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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