Colorectal cancer (CRC) patients with mismatch repair-deficient (dMMR) tumors without MLH1 methylation or germline MMR pathogenic variants (PVs) were previously thought to have Lynch syndrome (LS). It’s now appreciated that they can have double somatic (DS) MMR PVs. We explored clinical characteristics between patients with DS tumors and LS in two population-based cohorts (Ohio 2013-2016, Iceland 2000-2009). All had tumor screening, germline sequencing was performed for all with dMMR tumors, tumor sequencing followed for patients with unexplained dMMR. Those with LS were more likely to have multiple tumors and stronger family histories of cancer. Isolated loss of MSH6 or PMS2 protein on the immunohistochemistry screening test also predicted LS. (By Rachel Pearlman, https://jmg.bmj.com/content/early/2019/03/15/jmedgenet-2018-105698 )