Coexisting germline variants of MLH1 and MSH6 in a patient with Lynch syndrome who had uterine and ovarian cancer
- PMID: 40160885
- PMCID: PMC11950450
- DOI: 10.1007/s13691-025-00753-2
Coexisting germline variants of MLH1 and MSH6 in a patient with Lynch syndrome who had uterine and ovarian cancer
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. This disease often causes a familial cluster of patients with malignant tumors. In this report, we describe a 37-year-old woman who presented with endometrioid carcinoma in the ovary and uterine corpus associated with Lynch syndrome. She carried two germline pathogenic variants, a recurrently reported MLH1 c.2250C > G (p.Tyr750*) and a previously unreported MSH6 c.2385del (p.Ile795Metfs*15). The tumor cells showed microsatellite instability. Immunohistochemistry for the endometrial tumor showed decreased MLH1 expression, loss of PMS2 expression, retained MSH2 expression, and loss of MSH6 expression, which suggests that both variants impair each protein stability and thus cause MMR deficiency. Whether these variants were inherited from her parents or occurred de novo was unknown. The tumor cells had somatic variants BRCA1 c.1016del and BRCA2 c.36dupT that might be due to secondary mutation by MMR deficiency. The use of an immune checkpoint inhibitor pembrolizumab resulted in durable partial response of metastatic lung tumors. This case reminds clinicians of the rare possibility of multiple germline variants in MMR genes in individuals with Lynch syndrome.
Keywords: BRCA1; BRCA2; Lynch syndrome; MLH1; MSH6.
© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2025. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
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