Germline genetic testing can aid in difficult diagnostic workups but may reveal variants of unknown significance (VUS), which do not alter patient management or provide definitive diagnoses and may worsen stress on patients and families. VUS are more prevalent in underrepresented populations given their absence in large scale genomic studies. We describe seven pediatric hematology/oncology patients seen in the highly diverse Bronx County in New York City in which VUS or novel pathogenic variant identification influenced clinical management and outcomes. These cases highlight the importance of incorporating underrepresented populations into genomic databases to improve variant characterization and address healthcare disparities.