ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3577G>A (p.Val1193Ile) (rs779148780)

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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 RCV000166645 SCV000217449 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000166645 SCV000904605 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515365 SCV000611360 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000590430 SCV000567024 uncertain significance not provided 2018-06-07 criteria provided, single submitter clinical testing This variant is denoted ATM c.3577G>A at the cDNA level, p.Val1193Ile (V1193I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Val1193Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the beta-adaptin interaction domain (Tavtigian 2009). 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 Val1193Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000166645 SCV000747796 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590430 SCV000694263 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The c.3577G>A (p.Val1193Ile) variant involves the alteration of a conserved nucleotide located in the first nucleotide of exon 25 in the ATM gene. The variant lies within the Armadillo-like helical domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts that this variant may introduce an SF2/ASF ESE site at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.0000083 (1/120766 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories have classified this variant as being of uncertain significance. To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable databases, nor has it been 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.
Invitae RCV000200001 SCV000254087 uncertain significance Ataxia-telangiectasia syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1193 of the ATM protein (p.Val1193Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs779148780, ExAC 0.002%) but has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186973). 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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