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Somatic mutagenesis to create specific cancer gene mutant variants in situ is not a feasible research approach before the CRISPR/Cas9 gene editing technology and the next generation sequencing (NGS) analysis are available. Here we described an inducible Cas9 effector/CRISPR mutagen (ICE CRIM) mouse model to perform somatic mutagenesis on the well-known Trp53 tumor suppressor gene, and two key players, Mlh1 and Msh2, in DNA mismatch repair (MMR). In our model, we observed global MMR deficiency accelerated Trp53 mutant-driven hematopoietic neoplasm development. MMR deficient tumorous tissues displayed a microsatellite instability (MSI) phenotype. A common hypothesis for MMR deficiency caused tumorigenesis is the accumulation of frame-shift mutations in the coding mononucleotide repeat (cMNR) of downstream cancer gene targets. Due to the genome sequence differences in mouse and human, the MSI targets are not identical in the two species thus raise the discussion on the conservation of the causes of MMR-deficient tumor development. We used a customized probe capture technology to enrich for the mouse counterpart of the human MSI-targeted cMNRs in tumors for next generation sequencing analysis. Our results suggest a conservation on the MMR deficiency-caused tumorigenesis between the two species.