In an effort to discover inherited genetic variants that influence biological and clinical characteristics of familial CRC developed in unrelated high-risk patients, who previously tested negative for pathogenic variants in MMR genes, we examined 44 cancer associated genes using next generation sequencing (NGS), and applied minigene-based assay to analyze the impact of a subset of genetic variants on RNA splicing. This evidence concerns the gene MRC1 and colorectal carcinoma.