ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2443A>G (p.Ile815Val) (rs746090916)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580991 SCV000682055 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000236281 SCV000293998 uncertain significance not provided 2018-10-25 criteria provided, single submitter clinical testing This variant is denoted ATM c.2443A>G at the cDNA level, p.Ile815Val (I815V) 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 a pathogenic or benign germline variant. ATM Ile815Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Ile815Val 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 Ile815Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780914 SCV000918561 uncertain significance not specified 2018-09-07 criteria provided, single submitter clinical testing Variant summary: ATM c.2443A>G (p.Ile815Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245960 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2443A>G in individuals affected with Ataxia-Telangiectasia or Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000476330 SCV000546833 uncertain significance Ataxia-telangiectasia syndrome 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 815 of the ATM protein (p.Ile815Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs746090916, ExAC 0.01%) but has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 246438). 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 rare 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.

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