ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3059C>T (p.Thr1020Ile) (rs186626274)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220730 SCV000275217 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000220730 SCV000682099 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-14 criteria provided, single submitter clinical testing
GeneDx RCV000587502 SCV000564625 uncertain significance not provided 2018-03-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.3059C>T at the cDNA level, p.Thr1020Ile (T1020I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr1020Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Thr1020Ile is located within a region that interacts with beta-adaptin (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 information, it is unclear whether ATM Thr1020Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587502 SCV000694247 uncertain significance not provided 2017-05-08 criteria provided, single submitter clinical testing Variant summary: The ATM c.3059C>T (p.Thr1020Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. This variant is located in the Armadillo-type fold (IPR016024) (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 1/120648 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant was reported in one patient without co-occurrence or co-segregation data. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Due to the paucity of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS).
Invitae RCV000204390 SCV000260339 uncertain significance Ataxia-telangiectasia syndrome 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1020 of the ATM protein (p.Thr1020Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs186626274, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 220080). 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 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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