Diagnostic Challenges due to a Germline Missense MSH2 Variant in a Patient With Immunotherapy-Responsive Locally Advanced Rectal Adenocarcinoma.

backgroundRapid and accurate identification of mismatch repair (MMR) deficiency and Lynch syndrome is critical in the prognostication and clinical management of patients with colorectal carcinoma. CASE DESCRIPTION: We describe here a young woman who developed a locally aggressive rectal adenocarcinoma with intact MMR protein expression by immunohistochemistry and absence of histologic evidence of MMR deficiency-associated increased tumoral immune response. Germline DNA-targeted sequencing identified MSH2 variant p.R711P, initially classified as a variant of undetermined significance. Somatic tumoral DNA analysis revealed the identical MSH2 variant, high tumor mutational burden, and microsatellite instability, in addition to superimposed alterations in β2-microglobulin gene, possibly explaining the altered intratumoral immunity. Consequently, the patient was started on immunotherapy, leading to successful disease control (33 month follow-up).

conclusionThe findings emphasize the utility of an integrative approach in the assessment of MMR status for determining candidacy for immunotherapy, especially in the setting of missense variants in MMR genes.