Our custom-designed tumor sequencing assay enabled the investigation of multiple causes of dMMR simultaneously including SLS cases with unusual patterns of protein loss by IHC, including an SLS case with loss of all four MMR proteins that harbored double somatic mutations in MLH1 and in MSH6. Furthermore, evaluation of multiple NGS-derived tumor features namely TMB, INDEL count, multiple MSI calling tools and COSMIC TMS enabled accurate dMMR prediction to support the MMR IHC result. Here, MSH6 is linked to neoplasm.