Differential detection of BRCA-associated cancer risk and Lynch syndrome in genomic screening.

Abstract

e13537 Background: Hereditary cancer syndromes such as BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) account for many preventable cancers. Identification of carriers often relies on family history, guideline-based testing, or cancer diagnosis, leading to missed prevention opportunities. Voluntary population genomic screening allows assessment of how participation patterns influence detection of hereditary cancer risk. The Healthy Nevada Project (HNP), a voluntary genomic screening program in Northern Nevada, enables real-world assessment of hereditary cancer risk in a community cohort. With approximately 10% participation of the region’s adult population, HNP allows population-level comparison of observed prevalence with national benchmarks and condition-specific enrichment. Methods: We analyzed 48,143 Healthy Nevada Project participants with demographic and exome-derived variant data. Pathogenic or likely pathogenic variants in BRCA1/2 and Lynch syndrome mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM) were identified. Crude prevalence estimates were calculated and compared with widely cited national benchmarks. BRCA1/2 prevalence was examined by sex to assess patterns relevant to genetic testing. Results: HBOC prevalence was 0.733% (1 in 136), exceeding national expectations of approximately 0.20–0.33% (1 in 300–500) reported by the CDC. In contrast, LS prevalence was 0.332% (1 in 301), closely matching the widely cited national rate of approximately 0.36% (1 in 279) referenced in CDC Lynch syndrome materials. The overall cohort was predominantly female (67.8% female, 32.2% male). Despite this imbalance, BRCA1/2 pathogenic variant prevalence was comparable between men and women, consistent with autosomal inheritance. Conclusions: In this voluntary genomic screening cohort, BRCA-associated cancer risk appeared enriched relative to national estimates, whereas LS prevalence aligned with population expectations. These findings should be interpreted in the context of substantial self-selection, including greater participation by women, older adults, and those with family history. Notably, comparable BRCA1/2 prevalence across sexes despite lower male participation highlights persistent gaps in awareness and testing of male carriers, despite their elevated risks for prostate and gastrointestinal malignancies. The contrasting prevalence patterns suggest that condition-specific awareness and perceived cancer risk preferentially enrich BRCA-associated findings while leaving LS under-recognized. Reliance on voluntary pathways may therefore contribute to missed opportunities for early surveillance and cascade testing, underscoring the value of upstream genomic risk identification to support more equitable detection of hereditary cancer syndromes in oncology care.