Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome With Disease Risk in Adults According to Family History

This cohort study uses data from the UK Biobank to assess the prevalence and clinical importance of pathogenic or likely pathogenic variants associated with genomic conditions of familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome. Importance Pathogenic DNA variants associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome are widely recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening. Objectives To assess the prevalence and clinical importance of pathogenic or likely pathogenic variants associated with each of 3 genomic conditions (familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome) within the context of contemporary clinical care. Design, Setting, and Participants This cohort study used gene-sequencing data from 49 & x202f;738 participants in the UK Biobank who were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. Inpatient hospital data date back to 1977; cancer registry data, to 1957; and death registry data, to 2006. Statistical analysis was performed from July 22, 2019, to November 15, 2019. Exposures Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist. Main Outcomes and Measures Composite end point specific to each genomic condition based on atherosclerotic cardiovascular disease events for familial hypercholesterolemia, breast or ovarian cancer for hereditary breast and ovarian cancer syndrome, and colorectal or uterine cancer for Lynch syndrome. Results Among 49 & x202f;738 participants (mean [SD] age, 57 [8] years; 27 & x202f;144 female [55%]), 441 (0.9%) harbored a pathogenic or likely pathogenic variant associated with any of 3 genomic conditions, including 131 (0.3%) for familial hypercholesterolemia, 235 (0.5%) for hereditary breast and ovarian cancer syndrome, and 76 (0.2%) for Lynch syndrome. Presence of these variants was associated with increased risk of disease: for familial hypercholesterolemia, 28 of 131 carriers (21.4%) vs 4663 of 49 & x202f;607 noncarriers (9.4%) developed atherosclerotic cardiovascular disease; for hereditary breast and ovarian cancer syndrome, 32 of 116 female carriers (27.6%) vs 2080 of 27 & x202f;028 female noncarriers (7.7%) developed associated cancers; and for Lynch syndrome, 17 of 76 carriers (22.4%) vs 929 of 49 & x202f;662 noncarriers (1.9%) developed colorectal or uterine cancer. The predicted probability of disease at age 75 years despite contemporary clinical care was 45.3% for carriers of familial hypercholesterolemia, 41.1% for hereditary breast and ovarian cancer syndrome, and 38.3% for Lynch syndrome. Across the 3 conditions, 39.7% (175 of 441) of the carriers reported a family history of disease vs 23.2% (34 & x202f;517 of 148 & x202f;772) of noncarriers. Conclusions and Relevance The findings suggest that approximately 1% of the middle-aged adult population in the UK Biobank harbored a pathogenic variant associated with any of 3 genomic conditions. These variants were associated with an increased risk of disease despite contemporary clinical care and were not reliably detected by family history. Question What is the prevalence and clinical importance of pathogenic DNA variants in genes associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome in a national biobank? Findings In this cohort study of 49 & x202f;738 participants in the UK Biobank, a pathogenic or likely pathogenic variant associated with the 3 genomic conditions was identified in 0.9% of participants. These individuals had an increased risk of disease identified by gene sequencing that was not found through self-reported family history. Meaning The findings suggest that some participants in the UK Biobank harbored a pathogenic variant associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, or Lynch syndrome and may have an increased risk of disease even within the context of routine clinical care; genomic screening efforts may enhance detection and treatment for these individuals.