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Germline CHEK2 variants were extracted from UK Biobank (n=469,765) and Geisinger MyCode (n=170,503) using exome-sequenced biobanks linked to electronic health records. Variants were classified by ACMG/AMP criteria and association analysis used SAIGE-GENE+ with Bonferroni correction. Results showed increased risk across tested cancers, earlier age-dependent penetrance, and cohort-specific effects on overall survival. Tailored management strategies are warranted.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/genomic-ascertainment-of-chek2-related-cancer-predisposition/332554/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/genomic-ascertainment-of-chek2-related-cancer-predisposition/332554.png","ImageObject",300,407,{"name":92,"@type":93},"Riley","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main goal of the study on CHEK2-related predisposition?","Question",{"text":112,"@type":113},"To quantify cancer risk in individuals carrying CHEK2 germline pathogenic/likely pathogenic heterozygous variants using genomic ascertainment in two large population cohorts.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were CHEK2 variants obtained and classified in this research?",{"text":117,"@type":113},"Germline CHEK2 variants were extracted from UK Biobank and Geisinger MyCode exome-sequenced biobanks linked to electronic health records, then classified using ACMG/AMP criteria.",{"name":119,"@type":110,"acceptedAnswer":120},"What did the results show about cancer risk and penetrance in CHEK2 heterozygotes?",{"text":121,"@type":113},"CHEK2 heterozygotes had a significant excess risk of all tested cancers and earlier age-dependent cancer penetrance in both cohorts.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},332554,1790372834,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":34,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},1374391975076,"https://ap-avatar.wpscdn.com/avatar/14000253ca4ec9f6853?x-image-process=image/resize,m_fixed,w_180,h_180&k=1783305029341752051","medRxiv preprint doi: [https://doi.org/10.1101/2024.08.07.24311613](https://doi.org/10.1101/2024.08.07.24311613); this version posted August 8, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  \nThis article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available  \nfor use under a CC0 license.  \nGenomic ascertainment of CHEK2-related cancer predisposition  \nRunning head: CHEK2-related cancer predisposition  \n*Sun Young Kim, MD, Ph.D 1,2, *Jung Kim, Ph.D 1, Mark Ramos, Ph.D 1, Jeremy Haley, MS3, Diane Smelser, Ph.D3, H. Shanker Rao, MS3, Uyenlinh L. Mirshahi, Ph.D3, Geisinger-Regeneron DiscovEHR Collaboration, Barry I. Graubard, Ph.D4, Hormuzd A. Katki, Ph.D4, David Carey, Ph.D3, Douglas R.  \nStewart, MD 1  \n1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA, 2Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA, 3 Department of Genomic Health, Geisinger, Danville, PA, USA, 4Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA  \n*Sun Young Kim and *Jung Kim contributed to equally to this research.  \nCorrespondence to: Douglas R. Stewart  \nAddress: 9609 Medical Center Drive Rm 6E450, Bethesda, MD, 20892  \nTel: 240-276-7238; Fax: 240-276-7836.  \nEmail: [drstewart@mail.nih.gov](drstewart@mail.nih.gov)  \nAcknowledgments: This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Bethesda, MD and utilized the computational resources of the NIH High-Performance Computing Biowulf cluster. This research has been conducted using the UK Biobank Resources under application 54389.  \n1  \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.  \nmedRxiv preprint doi: [https://doi.org/10.1101/2024.08.07.24311613](https://doi.org/10.1101/2024.08.07.24311613); this version posted August 8, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  \nThis article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available  \nfor use under a CC0 license.  \nPrevious presentations: Portions ofthis investigation were presented as a platform presentation at the  \nannual meeting of the American College of Medical Genetics and Genomics in Salt Lake City, Utah, March 2023.  \nmedRxiv preprint doi: [https://doi.org/10.1101/2024.08.07.24311613](https://doi.org/10.1101/2024.08.07.24311613); this version posted August 8, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  \nThis article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available  \nfor use under a CC0 license.  \nAbstract  \nPurpose. There is clear evidence that deleterious germline variants in CHEK2 increases risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Genomic ascertainment was used to quantify cancer risk in CHEK2 germline pathogenic variant heterozygotes.  \nPatients and Methods. Germline CHEK2 variants were extracted from two exome-sequenced biobanks linked to the electronic health record: UK Biobank (n= 469,765) and Geisinger MyCode (n=170,503) .  \nVariants were classified as per American College of Medical Genetics and Genomics  \n(ACMG)/Association for Molecular Pathology (AMP) criteria. Heterozygotes harbored a CHEK2 pathogenic/likely pathogenic (P/LP) variant; controls harbored benign/likely benign ","cbCailuyTBm9jgtL","https://ap.wps.com/l/cbCailuyTBm9jgtL","pdf",2167315,25,"English","# Abstract\n## Purpose\n## Patients and Methods\n## Results\n## Conclusion","[{\"question\":\"What is the main goal of the study on CHEK2-related predisposition?\",\"answer\":\"To quantify cancer risk in individuals carrying CHEK2 germline pathogenic/likely pathogenic heterozygous variants using genomic ascertainment in two large population cohorts.\"},{\"question\":\"How were CHEK2 variants obtained and classified in this research?\",\"answer\":\"Germline CHEK2 variants were extracted from UK Biobank and Geisinger MyCode exome-sequenced biobanks linked to electronic health records, then classified using ACMG/AMP criteria.\"},{\"question\":\"What did the results show about cancer risk and penetrance in CHEK2 heterozygotes?\",\"answer\":\"CHEK2 heterozygotes had a significant excess risk of all tested cancers and earlier age-dependent cancer penetrance in both cohorts.\"}]","Genomic ascertainment of CHEK2-related cancer predisposition | PDF",1789998701,63]