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To understand the frequency of germline variants in the <jats:italic>CHEK2<\/jats:italic> gene and their impact on pediatric malignancies, we used whole\u2010exome sequencing to search for <jats:italic>CHEK2<\/jats:italic> variants in the germlines of 418 children diagnosed with cancer in our clinics. Moreover, we performed functional analysis of the pathogenic <jats:italic>CHEK2<\/jats:italic> variants to analyze the effect of the alterations on CHK2 protein function. We detected a <jats:italic>CHEK2<\/jats:italic> germline variant in 32\/418 (7.7%) pediatric cancer patients and 46.8% of them had leukemia. Functional analysis of the pathogenic variants revealed that 5 pathogenic variants impaired CHK2 protein function. 6\/32 patients carried one of these clearly damaging <jats:italic>CHEK2<\/jats:italic> variants and two of them harbored a matching family history of cancer. In conclusion, we detected germline <jats:italic>CHEK2<\/jats:italic> variants in 7.7% of all pediatric cancer patients, of which a minority but still relevant fraction of approximately 20% had a profound impact on protein expression or its phosphorylation after irradiation\u2010induced DNA damage. Accordingly, we conclude that <jats:italic>CHEK2<\/jats:italic> variants increase the risk for not only adult\u2010onset but also pediatric cancer.<\/jats:p>","DOI":"10.1002\/ijc.34390","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T08:39:42Z","timestamp":1670229582000},"page":"1388-1398","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The CHK2 kinase is recurrently mutated and functionally impaired in the germline of pediatric cancer patients"],"prefix":"10.1002","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5394-0907","authenticated-orcid":false,"given":"Rabea","family":"Wagener","sequence":"first","affiliation":[{"name":"Department of Pediatric Oncology Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University D\u00fcsseldorf  D\u00fcsseldorf Germany"},{"name":"German Cancer Consortium (DKTK) partner site Essen\/D\u00fcsseldorf  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