ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7919C>T (p.Thr2640Ile) (rs4988125)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130402 SCV000185262 likely benign Hereditary cancer-predisposing syndrome 2019-05-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000586791 SCV000209649 uncertain significance not provided 2018-07-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.7919C>T at the cDNA level, p.Thr2640Ile (T2640I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has been observed in several individuals with breast cancer, as well as in an individual undergoing multigene hereditary cancer panel testing, but has also been observed in healthy or cancer-free individuals (Tavtigian 2009, Bodian 2014, Mu 2016, Tung 2016, Decker 2017). ATM Thr2640Ile was observed at an allele frequency of 0.021% (26/126,328) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Thr2640Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000168144 SCV000218804 uncertain significance Ataxia-telangiectasia syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2640 of the ATM protein (p.Thr2640Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs4988125, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 26976419, 20305132, 29522266) and in an unaffected control population (PMID: 30287823). In a large meta-analysis studying the association of ATM missense variants with increased risk of breast cancer, this c.7919C>T substitution showed no evidence for increased cancer risk (0/4,112 cases vs. 1/2,399 controls) (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 133634). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 RCV000120159 SCV000694364 uncertain significance not specified 2019-07-10 criteria provided, single submitter clinical testing Variant summary: ATM c.7919C>T (p.Thr2640Ile) 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 8.3e-05 in 301974 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (9.1e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.7919C>T, has been reported in the literature in individuals affected with Breast- and/or Ovarian Cancer (Bernstein_2010, Tung_2014, Hauke_2018, Schubert_2019) as well as in control cohorts (Tavtigian_2009, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (4x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000168144 SCV000745133 likely benign Ataxia-telangiectasia syndrome 2017-03-06 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000586791 SCV000805621 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing
Color RCV000130402 SCV000910632 likely benign Hereditary cancer-predisposing syndrome 2014-12-17 criteria provided, single submitter clinical testing
ITMI RCV000120159 SCV000084301 not provided not specified 2013-09-19 no assertion provided reference population
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000168144 SCV000732996 likely benign Ataxia-telangiectasia syndrome no assertion criteria provided clinical testing

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