ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8993T>C (p.Ile2998Thr) (rs778670498)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227223 SCV000283101 uncertain significance Ataxia-telangiectasia syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2998 of the ATM protein (p.Ile2998Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs778670498, 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: 236795). 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 threonine 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.
Ambry Genetics RCV000569551 SCV000665485 likely benign Hereditary cancer-predisposing syndrome 2016-02-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000569551 SCV000687867 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590595 SCV000694389 uncertain significance not provided 2016-10-14 criteria provided, single submitter clinical testing Variant summary: The ATM c.8993T>C (p.Ile2998Thr) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this substitution. This variant was found in 1/121384 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. A clinical diagnostic laboratory classified this variant as uncertain significance. 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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