Colorectal cancer (CRC) is a leading cause of cancer-related death, with incidence rising substantially among individuals under 50 years of age. Polygenic risk scores (PRS) hold promise for identifying high-risk individuals; when combined with lifestyle factors, they substantially improve prediction accuracy compared with models based on lifestyle factors alone. However, few clinical tools currently exist that facilitate this integrated, PRS-enhanced risk assessment. To bridge this gap, we developed MyGeneRisk Colon, a publicly accessible web portal that delivers individualized CRC risk prediction by incorporating genetic, demographic, family history, and lifestyle factors. This paper details the development of the underlying risk prediction model, the portal’s architecture and data security, our reporting framework, and engagement with a community advisory panel. Designed as a user-friendly platform, MyGeneRisk Colon aims to effectively communicate personalized CRC risk profiles and educate users and healthcare providers about prevention strategies.

J.K.L. is supported by NCI (R37CA276306) and an investigator-initiated industry grant from Polymedco. He has no other conflicts and none of the above funded grants impact or affect the findings of this manuscript. A.T.C. served as a consultant to Pfizer Inc., Boehringer Ingelheim for work unrelated to this manuscript. He has also received research support from Freenome Holdings. C.G. owns stock in 23andMe, Inc. S.O. served as an advisor for Sanofi Pasteur SA. U.P. was a consultant with AbbVie and her family was or is holding individual stocks for the following companies: Alphabet Inc CL C, Amazon Com Inc, Aptera Motors Corp, ARM Holdings PLC, BioNTech, Boeing Company, BYD Company Limited, Crowdstrike Holdings Inc, Curvac BV, Microsoft Corp, MicroStrategy Inc, NVIDIA Corp, Stellantis, Tesla Inc, Walt Disney CO.

Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services R01 CA244588, P50 CA285275, R01 CA273198, R01 CA 297681. Genotyping/Sequencing services were provided by the Center for Inherited Disease Research (CIDR) contract number HHSN268201700006I and HHSN268201200008I. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704 and NIH/NHGRI HG008657. Scientific Computing Infrastructure at Fred Hutch funded by ORIP grant S10OD028685. This work was supported (in part) by the Thomas B. and Jeannette E. Laws McCabe Fund at the University of Pennsylvania to Jiayin Zheng. BWHS: National Institutes of Health U01 CA164974. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR) and/or the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include any of the following: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Illinois, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island,, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming. The authors assume full responsibility for analyses and interpretation of these data. CLUE II funding was from the National Cancer Institute (U01 CA086308, Early Detection Research Network; P30 CA006973), National Institute on Aging (U01 AG018033), and the American Institute for Cancer Research CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II (CPS-II) cohort. Harvard cohorts: HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, and R35 CA197735), NHS by the National Institutes of Health (P01 CA087969, UM1 CA186107, R01 CA137178, R01 CA151993, and R35 CA197735), and PHS by the National Institutes of Health (R01 CA042182). Effort of S. Ogino related to the GECCO and Harvard cohorts was additionally supported by the American Cancer Society Clinical Research Professor Award (CRP-24-1185864-01-PROF). Japan Public Health Center-based Prospective Study was supported by the National Cancer Center Research and Development Fund (23-A-31[toku], 26-A-2, 29-A-4, 2020-J-4, and 2023-J-4) (since 2011) and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010). MCCS: Melbourne Collaborative Cohort Study (MCCS): MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian National Health and Medical Research Council grants 209057, 396414 and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR). MEC: National Institutes of Health (R37 CA054281, P01 CA033619, R01CA126895, and U01 CA164973). PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Funding was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. SCCS: National Institutes of Health U01 CA202979 SMC_COSM (Swedish Mammography Cohort and Cohort of Swedish Men): This work is supported by the Swedish Research Council / SIMPLER Research Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institute's Distinguished Professor Award to Alicja Wolk. UK Biobank: This research has been conducted using the UK Biobank Resource under Application Number 8614 VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts 75N92021D00001,75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005

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