Familial Colorectal Cancer Type X (FCCTX) is a term used to describe a group of families with an increased predisposition to colorectal and other related cancers, but an unknown genetic basis. Whole-exome sequencing in two cancer-affected and one healthy members of a FCCTX family revealed a truncating germline mutation in PTPRT [c.4090dup, p.(Asp1364GlyfsTer24)]. PTPRT encodes a receptor phosphatase and is a tumor suppressor gene found to be frequently mutated at somatic level in many cancers, having been proven that these mutations act as drivers that promote tumor development. This germline variant shows a compatible cosegregation with cancer in the family and results in the loss of a significant fraction of the second phosphatase domain of the protein, which is essential for PTPRT’s activity. In addition, the tumors of the carriers exhibit epigenetic inactivation of the wild-type allele and an altered expression of PTPRT downstream target genes, consistent with a causal role of this germline mutation in the cancer predisposition of the family. Although PTPRT’s role cancer initiation and progression has been well studied, this is the first time that a germline PTPRT mutation is linked with cancer susceptibility and hereditary cancer, which highlights the relevance of the present study.