ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1096A>G (p.Ile366Val) (rs879254198)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235318 SCV000293782 uncertain significance not provided 2015-12-31 criteria provided, single submitter clinical testing This variant is denoted ATM c.1096A>G at the cDNA level, p.Ile366Val (I366V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ile366Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Ile366Val occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Ile366Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000472191 SCV000547150 uncertain significance Ataxia-telangiectasia syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 366 of the ATM protein (p.Ile366Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 246292). 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, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000563082 SCV000660781 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000780895 SCV000918530 uncertain significance not specified 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The ATM c.1096A>G (p.Ile366Val) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 245618 control chromosomes. In addition, two clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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