A Lynch Syndrome Family With Germline MLH1 c.931A>G Showing Preserved Tumor MMR Immunostaining but MSI‐H Status: A Case Report
TL;DR
This case highlights that preserved tumor MMR immunostaining does not exclude Lynch syndrome when clinical suspicion is high and Concurrent MSI and MMR immunohistochemistry, interpreted together with tumor sequencing and germline testing, may improve diagnosis, treatment selection, and familial risk assessment.
Abstract
Lynch syndrome screening may be complicated by discordant tumor testing results. We report a family carrying the germline MLH1 c.931A>G (p.Lys311Glu) variant in which both the proband and his father had colorectal tumors with retained mismatch repair protein expression by immunohistochemistry but microsatellite instability‐high status on tumor sequencing. The proband was a 39‐year‐old man with colorectal cancer and a family history fulfilling Amsterdam criteria. Paired tumor‐blood sequencing identified MSI‐H, high tumor mutational burden, and the germline MLH1 variant. The father showed a similar molecular profile and achieved substantial lesion regression after immunotherapy. Family studies demonstrated segregation of the variant across three generations. This case highlights that preserved tumor MMR immunostaining does not exclude Lynch syndrome when clinical suspicion is high. Concurrent MSI and MMR immunohistochemistry, interpreted together with tumor sequencing and germline testing, may improve diagnosis, treatment selection, and familial risk assessment.