ClinVar Miner

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

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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 RCV000130648 SCV000185527 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-08 criteria provided, single submitter clinical testing The p.I1688T variant (also known as c.5063T>C), located in coding exon 33 of the ATM gene, results from a T to C substitution at nucleotide position 5063. The isoleucine at codon 1688 is replaced by threonine, an amino acid with similar properties. This alteration has been reported with a carrier frequency of 0.00043 in 7051 unselected women with breast cancer and 0.00107 in 11241 female controls; and with a carrier frequency of 0.0000 in 53 unselected men with breast cancer and 0.0007 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 2020-10-29 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 been observed in individual(s) with breast cancer, as well as unaffected individuals (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 141932). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C2). 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. 5
Color Health, Inc RCV000130648 SCV000687604 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Natera, Inc. RCV000538544 SCV001452308 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001535791 SCV001749950 not provided Ataxia-telangiectasia syndrome; Malignant tumor of breast no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 02-10-2020 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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