Purpose Breast cancer (BC) risk prediction allows systematic identification of individuals at highest and lowest risk. We extend the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk model to incorporate the effects of polygenic risk scores (PRS) and other risk factors (RFs). Methods BOADICEA incorporates the effects of truncating variants in BRCA1 , BRCA2 , PALB2 , CHEK2 , and ATM ; a PRS based on 313 single-nucleotide polymorphisms (SNPs) explaining 20% of BC polygenic variance; a residual polygenic component accounting for other genetic/familial effects; known lifestyle/hormonal/reproductive RFs; and mammographic density, while allowing for missing information. Results Among all factors considered, the predicted UK BC risk distribution is widest for the PRS, followed by mammographic density. The highest BC risk stratification is achieved when all genetic and lifestyle/hormonal/reproductive/anthropomorphic factors are considered jointly. With all factors, the predicted lifetime risks for women in the UK population vary from 2.8% for the 1st percentile to 30.6% for the 99th percentile, with 14.7% of women predicted to have a lifetime risk of ≥17–<30% (moderate risk according to National Institute for Health and Care Excellence [NICE] guidelines) and 1.1% a lifetime risk of ≥30% (high risk). Conclusion This comprehensive model should enable high levels of BC risk stratification in the general population and women with family history, and facilitate individualized, informed decision-making on prevention therapies and screening.

Purpose-The proliferation of gene-panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2 and ATM.Methods-The BC incidence was modelled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2 and ATM and other unobserved genetic effects using segregation analysis methods.Results-The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH-burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive-testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly. Conclusions-The model may be a valuable tool for counselling women who have undergone gene-panel testing for providing consistent risks and harmonizing their clinical management. A Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use

Background: The CanRisk Tool (https://canrisk.org) is the next-generation web interface for the latest version of the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) state-of-the-art risk model and a forthcoming ovarian cancer risk model. Methods: The tool captures information on family history, rare pathogenic variants in cancer susceptibility genes, polygenic risk scores, lifestyle/hormonal/clinical features, and imaging risk factors to predict breast and ovarian cancer risks and estimate the probabilities of carrying pathogenic variants in certain genes. It was implemented using modern web frameworks, technologies, and web services to make it extensible and increase accessibility to researchers and third-party applications. The design of the graphical user interface was informed by feedback from health care professionals and a formal evaluation. Results: This freely accessible tool was designed to be user friendly for clinicians and to boost acceptability in clinical settings. The tool incorporates a novel graphical pedigree builder to facilitate collection of the family history data required by risk calculations. Conclusions: The CanRisk Tool provides health care professionals and researchers with a user-friendly interface to carry out multifactorial breast and ovarian cancer risk predictions. It is the first freely accessible cancer risk prediction program to carry the CE marking. Impact: There have been over 3,100 account registrations, and 98,000 breast and ovarian cancer risk calculations have been run within the first 9 months of the CanRisk Tool launch.

PURPOSE To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management. METHODS We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment. RESULTS BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. CONCLUSION In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.