ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6998C>T (p.Thr2333Ile) (rs150503164)

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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 RCV000115240 SCV000184909 likely benign Hereditary cancer-predisposing syndrome 2018-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Color RCV000115240 SCV000910903 likely benign Hereditary cancer-predisposing syndrome 2016-04-22 criteria provided, single submitter clinical testing
GeneDx RCV000590099 SCV000149149 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.6998C>T at the cDNA level, p.Thr2333Ile (T2333I) 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 Thr2333Ile was observed at an allele frequency of 0.0874%(21/24,026) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Thr2333Ile is located in the FAT domain (Stracker 2013). 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 Thr2333Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590099 SCV000694340 uncertain significance not provided 2016-09-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.6998C>T (p.Thr2333Ile) variant involves the alteration of a conserved nucleotide and is present in FAT domain of the ATM protein. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 5/119466 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0004858 (5/10292). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), thus it is uncertain whether or not it represents a rare polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in literature, nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories in ClinVar have classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000206376 SCV000259774 uncertain significance Ataxia-telangiectasia syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2333 of the ATM protein (p.Thr2333Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs150503164, ExAC 0.05%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127435). 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 isoleucine 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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