ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7004C>T (p.Thr2335Ile) (rs3092831)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166521 SCV000217321 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000168468 SCV000219168 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2335 of the ATM protein (p.Thr2335Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs3092831, ExAC 0.1%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186867). 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 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.
GeneDx RCV000586878 SCV000292479 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.7004C>T at the cDNA level, p.Thr2335Ile (T2335I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant was reported in a multiethnic exome array study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Thr2335Ile was observed at an allele frequency of 0.07% (17/24024) 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Thr2335Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000855628 SCV000694341 uncertain significance not specified 2019-08-27 criteria provided, single submitter clinical testing Variant summary: ATM c.7004C>T (p.Thr2335Ile) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of 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 4.8e-05 in 251066 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (4.8e-05 vs 0.001), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.7004C>T in individuals affected with breast cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000168468 SCV000790698 uncertain significance Ataxia-telangiectasia syndrome 2017-04-05 criteria provided, single submitter clinical testing
Color RCV000166521 SCV000903897 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing

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