Abstract(#br)There are approximately 136,830 new colorectal cancer (CRC) cases diagnosed annually in the United States. In an effort to identify those at highest risk for Lynch Syndrome, an inherited CRC predisposition syndrome, several professional guidelines advocate for routine screening of all colorectal adenocarcinomas for features of DNA mismatch repair, microsatellite instability (MSI) and/or absent immunohistochemistry staining. Approximately 12–17 % of CRCs demonstrate MSI with germline mutations in genes involved in DNA mismatch repair, MLH1, MSH2, MSH6, PMS2 and TACSTD1/EPCAM and somatic MLH1 promotor hypermethylation being alternative pathways for the development of microsatellite unstable CRC. It is important to distinguish between these two events as the underlying cause of... cancer development as management and implications for the patient and family members vary significantly. We describe a patient with multiple primary cancers, a deleterious germline MSH6 mutation and somatic MLH1 promotor hypermethylation highlighting the importance of incorporating the clinical history with the genetic evaluation.