Influence of family history on penetrance of hereditary cancers in a population setting

BACKGROUND: We sought to investigate how penetrance of familial cancer syndromes varies with family history using a population-based cohort. METHODS: We analysed 454,712 UK Biobank participants with exome sequence and clinical data (data collected between March 2006 and June 2021). We identified participants with a self-reported family history of breast or colorectal cancer and a pathogenic/likely pathogenic variant in the major genes responsible for hereditary breast cancer or Lynch syndrome. We calculated survival to cancer diagnosis (controlled for sex, death, recruitment centre, screening and prophylactic surgery). FINDINGS: Women with a pathogenic BRCA1 or BRCA2 variant had an increased risk of breast cancer that was higher in those with a first-degree family history (relative hazard 10.3 and 7.8, respectively) than those without (7.2 and 4.7). Penetrance to age 60 was also higher in those with a family history (44.7%, CI 32.2–59.3 and 24.1%, CI 17.5–32.6) versus those without (22.8%, CI 15.9–32.0 and 17.9%, CI 13.8–23.0). A similar pattern was seen in Lynch syndrome: individuals with a pathogenic MLH1, MSH2 or MSH6 variant had an increased risk of colorectal cancer that was significantly higher in those with a family history (relative hazard 35.6, 48.0 and 9.9) than those without (13.0, 15.4 and 7.2). Penetrance to age 60 was also higher for carriers of a pathogenic MLH1 or MSH2 variant in those with a family history (30.9%, CI 18.1–49.3 and 38.3%, CI 21.5–61.8) versus those without (20.5% CI 9.6–40.5 and 8.3% CI 2.1–30.4), but not for MSH6 (6.5% CI 2.7–15.1 with family history versus 8.3%, CI 5.1–13.2). Relative risk increases were also observed both within and across conditions. INTERPRETATION: Individuals with pathogenic cancer syndrome variants may be at a less elevated risk of cancer in the absence of a first-degree family history, so in the context of results return, family history should be considered when counselling patients on the risks and benefits of potential follow-up care. FUNDING: The current work is supported by the 10.13039/501100000265MRC (grant no MR/T00200X/1). The MRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.