ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5063T>C (p.Ile1688Thr) (rs199836342)

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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 RCV000130648 SCV000185527 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000484463 SCV000564644 uncertain significance not provided 2018-06-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.5063T>C at the cDNA level, p.Ile1688Thr (I1688T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Ile1688Thr was observed at an allele frequency of 0.09% (15/17246) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Ile1688Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000538544 SCV000622562 uncertain significance Ataxia-telangiectasia syndrome 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1688 of the ATM protein (p.Ile1688Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs199836342, ExAC 0.2%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141932). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
Color RCV000130648 SCV000687604 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194272 SCV001363666 likely benign not specified 2019-02-14 criteria provided, single submitter clinical testing Variant summary: ATM c.5063T>C (p.Ile1688Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 298714 control chromosomes (gnomAD and publication data), and was exclusively observed within the East Asian subpopulation at a frequency of 0.00092 in the gnomAD database. This frequency is slightly lower than expected for a pathogenic variant in ATM causing Breast Cancer (0.00092 vs 0.001), however the variant still might represent a benign polymorphism found predominantly in individuals of East Asian origin. Indeed, a large case-control association study, involving unselected breast cancer (BrC) patients and controls of Japanese ancestry, identified the variant in 3/7051 female BrC cases, but also found the variant in 12/11242 healthy female- and 9/12490 healthy male control individuals, based on their findings the authors of this study concluded that the variant is benign (Momozawa 2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as uncertain significance; however all of these classifications were performed before the publication of the Momozawa study. Based on the evidence outlined above, the variant was classified as likely benign.

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