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We present a case of a 27\u2010year\u2010old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, <jats:italic>MLH1<\/jats:italic> p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome\u2010associated cancers in three generations of the family and identified consistent <jats:italic>MLH1<\/jats:italic> loss. Whole\u2010exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy\u2010neutral loss of heterozygosity (LOH) occurring at the <jats:italic>MLH1<\/jats:italic> position in all tumors. This indicated that the germline variant and the copy\u2010neutral LOH led to biallelic loss of <jats:italic>MLH1<\/jats:italic> and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer\u2010associated genes such as <jats:italic>ARID1A<\/jats:italic> and <jats:italic>PIK3CA<\/jats:italic>. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome\u2010associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.<\/jats:p>","DOI":"10.1002\/gcc.23231","type":"journal-article","created":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T13:59:19Z","timestamp":1709992759000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Clonal origin and genomic diversity in Lynch syndrome\u2010associated endometrial cancer with multiple synchronous tumors: Identification of the pathogenicity of <scp><i>MLH1<\/i><\/scp> p.<scp>L582H<\/scp>"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6270-0753","authenticated-orcid":false,"given":"Kotaro","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology Niigata University Graduate School 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