ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6176C>T (p.Thr2059Ile) (rs144761622)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115226 SCV000186819 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000115226 SCV000902666 likely benign Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing
GeneDx RCV000588663 SCV000149135 uncertain significance not provided 2018-07-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.6176C>T at the cDNA level, p.Thr2059Ile (T2059I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has been observed in individuals with breast, colorectal, or endometrial cancer, but was also seen in control subjects (Bretsky 2003, Ho 2007, Hirsch 2008, Tavtigian 2009, Ring 2016, Yurgelun 2017). ATM Thr2059Ile was observed at an allele frequency of 0.36% (87/24,032) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the FAT domain (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 Thr2059Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000212040 SCV000593505 uncertain significance not specified 2016-09-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588663 SCV000694319 likely benign not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The c.6176C>T variant affects a conserved nucleotide, resulting in amino acid change from Thr to Ile. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 36/10302 ExAC African control chromosomes at a frequency of 0.00349, which is about 7 times of the maximum allele frequency of a ATM pathogenic variant (0.0005), suggesting this variant is benign. Taken together, this variant is classified as likely benign.
Invitae RCV000196722 SCV000252969 benign Ataxia-telangiectasia syndrome 2017-12-29 criteria provided, single submitter clinical testing
Mendelics RCV000196722 SCV000838567 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000588663 SCV000805596 uncertain significance not provided 2016-08-02 criteria provided, single submitter clinical testing

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