Variant of Uncertain Significance Patterns among Patients with Early-Onset Colorectal Cancer

The increasing burden of colorectal cancer among adults younger than age 50 years (early-onset colorectal cancer) and new National Comprehensive Cancer Network guidelines recommending universal genetic testing in early-onset colorectal cancer emphasize the need for accurate and timely variant classification in clinical care. In this study, we investigated germline variant of uncertain significance (VUS) patterns among diverse individuals with early-onset colorectal cancer. A total of 3,980 individuals ages 15 to 49 years when diagnosed with a first primary colorectal cancer, including 1,001 cases identifying as non-White, who underwent genetic testing for 14 colorectal cancer susceptibility genes performed by a clinical testing laboratory were included. A five-tier classification system was applied to all alterations to classify VUSs and was updated in March 2024. Disparities in variant reclassification rates emerged by self-identified race/ethnicity (P < 0.0001). A total of 4.8% of Ashkenazi Jewish, 18.2% of Asian, 12.2% of Black, 7.6% of Hispanic, and 6.7% of White individuals had at least one reclassified VUS. After reclassification, 356 individuals (8.9%) presented with 1+ VUSs. VUSs significantly varied by self-identified race/ethnicity (P = 0.008). Young individuals identifying as Black and Hispanic had significantly higher odds of presenting with a VUS compared with those identifying as White in multivariable logistic regression models. Individuals who identified as Black and Asian were significantly more likely to present with a VUS in PMS2 (OR = 3.59; 95% confidence interval, 1.73–7.48; P = 0.0006) and MSH2 (OR = 3.14; 95% confidence interval, 1.17–8.45; P = 0.02), respectively, compared with those identifying as White. These findings define unique VUS patterns in early-onset colorectal cancer by race and ethnicity, pointing to distinct germline variant spectra and to the potential for the discovery of novel ancestry-specific variants associated with early-onset colorectal cancer that will guide efforts to reduce clinical uncertainty and improve equitable care.

Among individuals with early-onset colorectal cancer, germline VUS reclassification as well as rates of VUSs in cancer susceptibility genes differed by self-identified race/ethnicity. These findings point to the importance of VUS reclassification as this may alter clinical management and to distinct germline variant spectra among diverse patients with early-onset colorectal cancer.