ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7775C>G (p.Ser2592Cys) (rs755009196)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166355 SCV000217143 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000230322 SCV000283062 uncertain significance Ataxia-telangiectasia syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 2592 of the ATM protein (p.Ser2592Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs755009196, ExAC <0.01%). This variant has been observed in individuals affected with breast cancer, prostate cancer, or Non-Hodgkin's lymphoma (PMID: 11606401, 11805335, 19781682, 29909963, 28825054, 17640065). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 186713). Experimental in vitro studies have shown that this missense change abolishes ATM kinase activity and increases radiosensitivity (PMID: 11805335). 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 RCV000236197 SCV000293440 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted ATM c.7775C>G at the cDNA level, p.Ser2592Cys (S2592C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has been reported in individuals with breast and prostate cancer, as well as in a healthy control (Dork 2001, Tavtigian 2009, Caminsky 2016, Abida 2017, Decker 2017). Scott et al. (2002) reported that ATM Ser2592Cys is associated with absent kinase activity and increased radiosensitivity in vitro, and the authors suggest that this variant produces a dominant interfering effect. ATM Ser2592Cys was not observed at a significant allele frequency 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 Ser2592Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000166355 SCV000687787 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-05 criteria provided, single submitter clinical testing
Academic Department of Medical Genetics, University of Cambridge RCV000166355 SCV000992205 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.

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