ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.290T>C (p.Ile97Thr) (rs786203011)

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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 RCV000166129 SCV000216900 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000200635 SCV000254076 uncertain significance Ataxia-telangiectasia syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 97 of the ATM protein (p.Ile97Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (no ExAC frequency). This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 186520). 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. 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.
GeneDx RCV000585916 SCV000292825 uncertain significance not provided 2018-08-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.290T>C at the cDNA level, p.Ile97Thr (I97T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has been observed in at least one individual with a personal history of a Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015). ATM Ile97Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with p53 and BRCA1 (Tavtigian 2009, Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Ile97Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000585916 SCV000694226 uncertain significance not provided 2016-09-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.290T>C (p.Ile97Thr) variant involves the alteration of a conserved nucleotide is located in in the telomere-length maintenance and DNA damage repair domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 117166 control chromosomes from ExAC. In literature, this variant is reported in one patient with Lynch syndrome-associated cancer and/or polyps (Yurgelun_2015) without strong evidence for pathogenicity. Multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Taken together, this variant is currently classified as variant of uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000585916 SCV000702266 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000767895 SCV000898526 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-09-28 criteria provided, single submitter clinical testing ATM NM_000051.3 exon 4 p.Ile97Thr (c.290T>C): This variant has been reported in the literature in 1 individual with a clinical suspicion of Lynch syndrome (Yurgelun 2015 PMID:25980754). This variant is present in 5/24000 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs786203011). This variant is present in ClinVar with several entries as "Variant of Uncertain Significance" (Variation ID:186520). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Color RCV000166129 SCV000906532 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing

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