ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6998C>T (p.Thr2333Ile) (rs150503164)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590099 SCV000149149 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.6998C>T at the cDNA level, p.Thr2333Ile (T2333I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Thr2333Ile was observed at an allele frequency of 0.0874%(21/24,026) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Thr2333Ile is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Thr2333Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115240 SCV000184909 likely benign Hereditary cancer-predisposing syndrome 2019-01-14 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
Invitae RCV000206376 SCV000259774 uncertain significance Ataxia-telangiectasia syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2333 of the ATM protein (p.Thr2333Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs150503164, ExAC 0.05%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127435). 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 isoleucine 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.
Integrated Genetics/Laboratory Corporation of America RCV000855568 SCV000694340 likely benign not specified 2019-08-05 criteria provided, single submitter clinical testing Variant summary: ATM c.6998C>T (p.Thr2333Ile) results in a non-conservative amino acid change located in the FAT domain (IPR003151) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-05 in 282418 control chromosomes (gnomAD), exclusively observed within the African or African-American subpopulation at a frequency of 0.00084. This frequency is somewhat smaller than expected maximum for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. However, this variant has also been reported in 6/2559 African American women (i.e. with an allele frequency of 0.0012) who were older than age 70 and cancer free (FLOSSIES database), supporting a benign role for the variant. The variant, c.6998C>T, has been reported in the literature in an individual affected with Lung adenocarcinoma (Parry_2017). This report does not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and reported the variant with conflicting assessments (likely benign (2x), VUS (2x)). Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000115240 SCV000910903 likely benign Hereditary cancer-predisposing syndrome 2016-04-22 criteria provided, single submitter clinical testing

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