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

Rapid and accurate identification of mismatch repair (MMR) deficiency and Lynch syndrome is critical in the prognostication and clinical management of patients with colorectal carcinoma.

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).

The 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.