Variant of uncertain significance (VUS) patterns among patients with early-onset colorectal cancer

The increasing burden of colorectal cancer among adults age<50 (early-onset CRC) and new National Comprehensive Cancer Network guidelines recommending universal genetic testing in early-onset CRC emphasize the need for accurate/timely variant classification in clinical care. Here, we investigated germline variant of uncertain significance (VUS) patterns among diverse individuals with early-onset CRC. A total of 3,980 individuals age 15-49 when diagnosed with a first primary CRC—including 1,001 cases identifying as non-White, who underwent genetic testing for 14 CRC 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 Ashkenazim, 18.2% of Asian, 12.2% of Black, 7.6% of Hispanic and 6.7% of White individuals had at least 1 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 versus Whites 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%CI=1.73-7.48;P=0.0006) and MSH2 (OR=3.14,95%CI=1.17-8.45;P=0.02), respectively, versus Whites. These findings define distinct VUS patterns in early-onset CRC by race and ethnicity, pointing to distinct germline variant spectra and to the potential for discovery of novel ancestry-specific variants associated with early-onset CRC that will guide efforts to reduce clinical uncertainty and improve equitable care.