ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5089A>G (p.Thr1697Ala) (rs142455912)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212027 SCV000149114 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing This variant is denoted ATM c.5089A>G at the cDNA level, p.Thr1697Ala (T1697A) at the protein level, and results in the change of a Threonine to an Alanine (ACC>GCC). This variant has been reported in individuals with breast cancer, Hodgkin's disease, and colorectal cancer (Offit 2002, Tavtigian 2009, Tung 2015, Decker 2017, Yurgelun 2017), as well as in an individual with intellectual disability with no specific information about cancer history provided (Grozeva 2015). A functional study of this variant from a breast cancer cell line showed no differences in the constitutive ATM protein level from levels of normal individuals (Ang?le 2003). ATM Thr1697Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Thr1697Ala is not located in a known functional domain. 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 Thr1697Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115205 SCV000184397 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-18 criteria provided, single submitter clinical testing Insufficient or Conflicting Evidence
Invitae RCV000200336 SCV000254119 likely benign Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515379 SCV000611366 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212027 SCV000805578 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing
Color RCV000115205 SCV000902827 likely benign Hereditary cancer-predisposing syndrome 2015-10-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779803 SCV000916607 uncertain significance not specified 2020-08-07 criteria provided, single submitter clinical testing Variant summary: ATM c.5089A>G (p.Thr1697Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 254138 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.3e-05 vs 0.004), allowing no conclusion about variant significance. c.5089A>G has been reported in the literature in individuals affected with Hodgkins disease, breast cancer, colorectal cancer, lung adenocarcinoma, and CLL (Offit_2002, Angele_2003, Tavtigian_2009, Tung_2015, Lu_2015, Young_2015, Yurgelun_2017, Tiao_2017, Parry_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or susceptibility to breast or other cancers. One publication reports experimental evidence showing that the cell lines from the breast cancer patient carrying c.5089A>G showed no differences in the constitutive ATM protein level (Angele_2003) although the authors did not provide any primary data substantiating this observation. Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.

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