Constitutional Mismatch Repair Deficiency (CMMRD) is caused by a biallelic mutation on one of the four major mismatch repair (MMR) genes. It is a rare autosomal recessive syndrome that predisposes to childhood cancer. We present a 21-year-old African American with metachronous non-Hodgkin lymphoma during childhood, bone marrow transplant due to relapse, and stage IV duodenal adenocarcinoma as a young adult. His original presentation merited CMMRD screening. As many chemotherapy agents cause DNA damage and require an intact MMR system, early diagnosis could have anticipated the lymphoma relapse due to drug resistance and started timely screening for other malignancies.