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Risks for other cancers remain unclear.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Cancer associations for coding variants in <jats:italic>ATM<\/jats:italic> and <jats:italic>CHEK2<\/jats:italic> were evaluated using whole-exome sequence data from UK Biobank linked to cancer registration data (348\u2009488 participants), and analysed both as a retrospective case-control and a prospective cohort study. Odds ratios, hazard ratios, and combined relative risks (RRs) were estimated by cancer type and gene. Separate analyses were performed for protein-truncating variants (PTVs) and rare missense variants (rMSVs; allele frequency &lt;0.1%).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>PTVs in <jats:italic>ATM<\/jats:italic> were associated with increased risks of nine cancers at p&lt;0.001 (pancreas, oesophagus, lung, melanoma, breast, ovary, prostate, bladder, lymphoid leukaemia (LL)), and three at p&lt;0.05 (colon, diffuse non-Hodgkin\u2019s lymphoma (DNHL), rectosigmoid junction). Carriers of rMSVs had increased risks of four cancers (p&lt;0.05: stomach, pancreas, prostate, Hodgkin\u2019s disease (HD)). RRs were highest for breast, prostate, and any cancer where rMSVs lay in the FAT or PIK domains, and had a Combined Annotation Dependent Depletion score in the highest quintile.<\/jats:p>\n                  <jats:p>PTVs in <jats:italic>CHEK2<\/jats:italic> were associated with three cancers at p&lt;0.001 (breast, prostate, HD) and six at p&lt;0.05 (oesophagus, melanoma, ovary, kidney, DNHL, myeloid leukaemia). Carriers of rMSVs had increased risks of five cancers (p&lt;0.001: breast, prostate, LL; p&lt;0.05: melanoma, multiple myeloma).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>PTVs in <jats:italic>ATM<\/jats:italic> and <jats:italic>CHEK2<\/jats:italic> are associated with a wide range of cancers, with the highest RR for pancreatic cancer in <jats:italic>ATM<\/jats:italic> PTV carriers. These findings can inform genetic counselling of carriers.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2024-110127","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T22:25:21Z","timestamp":1724970321000},"page":"1016-1022","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Protein-truncating and rare missense variants in <i>ATM<\/i> and <i>CHEK2<\/i> and associations with cancer in UK Biobank whole-exome sequence data"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4983-495X","authenticated-orcid":false,"given":"Toqir K","family":"Mukhtar","sequence":"first","affiliation":[{"name":"Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK"},{"name":"Department of Primary Care and Public Health, Imperial College London, London, 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