ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.649A>G (p.Ile217Val) (rs547045780)

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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 RCV000217843 SCV000275746 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000217843 SCV000687707 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-14 criteria provided, single submitter clinical testing
Counsyl RCV000472458 SCV000790108 uncertain significance Ataxia-telangiectasia syndrome 2017-03-06 criteria provided, single submitter clinical testing
GeneDx RCV000657028 SCV000566770 uncertain significance not provided 2018-04-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.649A>G at the cDNA level, p.Ile217Val (I217V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant was identified in 1/119 healthy Hispanic individuals undergoing whole genome sequencing (Bodian 2014); of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. ATM Ile217Val 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Ile217Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120164 SCV000084306 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000472458 SCV000546947 uncertain significance Ataxia-telangiectasia syndrome 2018-08-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 217 of the ATM protein (p.Ile217Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs547045780, ExAC 0.009%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 133639). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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