Abstract
Lynch syndrome is an autosomal dominant disorder caused by a heterozygous pathogenic germline variant in mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, PMS2, and EPCAM. Lynch syndrome often causes a familial cluster of patients with malignant tumors. We describe a 37-year-old woman who presented with endometrioid carcinoma in the ovary and endometrium associated with Lynch syndrome. She carried two germline pathogenic variants, a recurrently reported MLH1 c.2250C > G (p. Tyr750*) and previously unreported MSH6 c.2385del (p. Ile795Metfs*15). The tumor cells showed microsatellite instability. Immunohistochemistry showed decreased MLH1 expression, loss of PMS2 expression, retained MSH2 expression, and loss of MSH6 expression, indicating that both variants impair protein stability, causing MMR deficiency. Whether these variants were inherited from her parents or occurred de novo is unknown. The tumor cells had somatic variants BRCA1 c.1016del and BRCA2 c.36dupT, which might be due to secondary mutation by MMR deficiency. The use of pembrolizumab, an immune checkpoint inhibitor, resulted in a durable partial response of metastatic lung tumors. This case highlights the rare possibility of multiple germline variants in MMR genes in individuals with Lynch syndrome.