MSH2 and cancer: LS is caused by inherited defects in any of four key DNA mismatch repair (MMR) factors: MSH2, MLH1, MSH6, and PMS2. These genes are included on most cancer gene panel tests, and it is standard of care to screen them for pathogenic germline variants when their loss is observed in tumors by histology or by tests for microsatellite instability, the mutational consequence of MMR loss.