Ancestry-informative markers and variants of uncertain significance on hereditary cancer panels.

Introduction: Variants of uncertain significance (VUS) on multigene cancer panels can increase patient anxiety and lead to unnecessary interventions. Prior literature shows that, compared to Non-Hispanic Whites, VUS are more frequent among other racial and ethnic groups due to underrepresentation in population genetics databases. However, self-reported race/ethnicity is an imperfect proxy for genetic ancestry. Estimating genetic similarity using ancestry-informative markers may provide a more precise approach to assessing VUS frequency. Purpose: This study examined the association between genetic similarity and presence of VUS results among patients who underwent hereditary cancer panel testing. A sub-analysis in self-identified Hispanic participants assessed whether Indigenous American similarity was associated with VUS. Methods: Data were obtained from cancer patients in the Oncology Research Information Exchange Network (ORIEN), a national cancer research alliance. Patients were included if they underwent genetic counseling and multigene cancer panel testing. Genetic similarity was calculated based on ancestry-informative single nucleotide polymorphisms. Each participant received proportion estimates for seven ancestral groups: European, Indigenous American, East Asian, Middle Eastern, African, South Asian, and Oceanian. Predominant genetic similarity was defined as the ancestral group with the highest proportion estimate. Multivariable logistic regression was used to assess the association between genetic similarity and VUS. Results: The study included 597 participants and 50% had at least one VUS. Self-identified race/ethnicity included: 44% non-Hispanic White, 37% Hispanic White, 14% Asian, 2% non-Hispanic Black, and 3% unknown/multiracial. Self-reported race/ethnicity did not show a consistent association with VUS. Individuals whose predominant genetic similarity was non-European had increased odds of having a VUS compared to those with predominantly European genetic similarity: East Asian (OR = 2.06, 95% CI = 1.20-3.53), Middle Eastern (OR = 1.92, 95% CI = 1.03-3.56), African (OR = 2.48, 95% CI = 0.96-6.42), and Indigenous American (OR = 1.41, 95% CI = 0.92-2.17). Among self-reported Hispanics, when genetic similarity was measured continuously, every 10% increase in Indigenous American similarity was associated with a 11% increase in odds of having a VUS (OR: 1.11, 95% CI = 0.94-1.33). Conclusion: When assessed using ancestry-informative markers, non-European genetic similarity was associated with significantly increased odds of VUS results. Current reliance on self-reported race/ethnicity may mask the complexity of ancestry-related disparities in VUS occurrence.