{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T05:46:27Z","timestamp":1792043187210,"version":"4.4.0"},"reference-count":9,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T00:00:00Z","timestamp":1686787200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T00:00:00Z","timestamp":1686787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Margaret and Irene Stewardson Fund Scholarship"},{"name":"Melbourne Research Scholarship"},{"name":"NHMRC Investigator grant","award":["GNT1195099"],"award-info":[{"award-number":["GNT1195099"]}]},{"name":"National Health and Medical Research Council of Australia","award":["1125269"],"award-info":[{"award-number":["1125269"]}]},{"name":"NHMRC R.D. Wright Career Development Fellowship"},{"name":"Melbourne Dame Kate Campbell Fellowship"},{"DOI":"10.13039\/501100001782","name":"University of Melbourne","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001782","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Familial Cancer"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely\n                    <jats:italic>de novo<\/jats:italic>\n                    mosaic\n                    <jats:italic>MSH6<\/jats:italic>\n                    :c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syndrome\/Lynch-like syndrome. The patient developed MSH6-deficient EC and CRC at 54 and 58 years of age, respectively, without a detectable germline MMR pathogenic variant. Multigene panel sequencing of tumor and blood-derived DNA identified an\n                    <jats:italic>MSH6<\/jats:italic>\n                    somatic mutation (\n                    <jats:italic>MSH6<\/jats:italic>\n                    :c.1135_1139del p.Arg379*) common to both the EC and CRC, raising suspicion of mosaicism. A droplet digital polymerase chain reaction (ddPCR) assay detected the\n                    <jats:italic>MSH6<\/jats:italic>\n                    variant at 5.34% frequency in normal colonic tissue, 3.49% in saliva and 1.64% in blood DNA, demonstrating the presence of the\n                    <jats:italic>MSH6<\/jats:italic>\n                    variant in all three germ layers. This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling.\n                  <\/jats:p>","DOI":"10.1007\/s10689-023-00337-0","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T03:02:39Z","timestamp":1686798159000},"page":"423-428","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report"],"prefix":"10.1007","volume":"22","author":[{"given":"Romy","family":"Walker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Clendenning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihoon E.","family":"Joo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid","family":"Mahmood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Georgeson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Como","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharelle","family":"Joseland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan G.","family":"Preston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Jenkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Rosty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Finlay A.","family":"Macrae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Di Palma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainsley","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M.","family":"Winship","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel D.","family":"Buchanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,6,15]]},"reference":[{"key":"337_CR1","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1016\/j.cgh.2020.02.049","volume":"18","author":"AM Lucia Jansen","year":"2020","unstructured":"Lucia Jansen AM, Goel A (2020) Mosaicism in patients with Colorectal Cancer or Polyposis Syndromes: a systematic review. Clin Gastroenterol Hepatol 18:1949\u20131960. https:\/\/doi.org\/10.1016\/j.cgh.2020.02.049","journal-title":"Clin Gastroenterol Hepatol"},{"key":"337_CR2","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s10689-012-9568-9","volume":"12","author":"I Sourrouille","year":"2013","unstructured":"Sourrouille I, Coulet F, Lefevre JH et al (2013) Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Fam Cancer 12:27\u201333. https:\/\/doi.org\/10.1007\/s10689-012-9568-9","journal-title":"Fam Cancer"},{"key":"337_CR3","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1002\/ajmg.a.32620","volume":"149","author":"C Pastrello","year":"2009","unstructured":"Pastrello C, Fornasarig M, Pin E et al (2009) Somatic mosaicism in a patient with Lynch syndrome. Am J Med Genet 149:212\u2013215. https:\/\/doi.org\/10.1002\/ajmg.a.32620","journal-title":"Am J Med Genet"},{"key":"337_CR4","doi-asserted-by":"publisher","first-page":"e00699","DOI":"10.1002\/mgg3.699","volume":"7","author":"WR Geurts-Giele","year":"2019","unstructured":"Geurts-Giele WR, Rosenberg EH, van Rens A et al (2019) Somatic mosaicism by a de novo MLH1 mutation as a cause of Lynch syndrome. Mol Genet Genomic Med 7:e00699. https:\/\/doi.org\/10.1002\/mgg3.699","journal-title":"Mol Genet Genomic Med"},{"key":"337_CR5","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1038\/s41431-020-0689-6","volume":"28","author":"E Guillerm","year":"2020","unstructured":"Guillerm E, Svrcek M, Bardier-Dupas A et al (2020) Molecular tumor testing in patients with Lynch-like syndrome reveals a de novo mosaic variant of a mismatch repair gene transmitted to offspring. Eur J Hum Genet 28:1624\u20131628. https:\/\/doi.org\/10.1038\/s41431-020-0689-6","journal-title":"Eur J Hum Genet"},{"key":"337_CR6","doi-asserted-by":"publisher","DOI":"10.1101\/2023.02.27.23285541","author":"R Walker","year":"2023","unstructured":"Walker R, Mahmood K, Joo JE et al (2023) A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome. medRxiv. https:\/\/doi.org\/10.1101\/2023.02.27.23285541","journal-title":"medRxiv"},{"key":"337_CR7","doi-asserted-by":"publisher","first-page":"7452","DOI":"10.18632\/oncotarget.13918","volume":"8","author":"EA Kautto","year":"2017","unstructured":"Kautto EA, Bonneville R, Miya J et al (2017) Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS. Oncotarget 8:7452\u20137463. https:\/\/doi.org\/10.18632\/oncotarget.13918","journal-title":"Oncotarget"},{"key":"337_CR8","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1053\/j.gastro.2016.10.040","volume":"152","author":"AML Jansen","year":"2017","unstructured":"Jansen AML, Crobach S, Geurts-Giele WRR et al (2017) Distinct patterns of somatic mosaicism in the APC gene in Neoplasms from patients with unexplained adenomatous polyposis. Gastroenterology 152:546\u2013549e3. https:\/\/doi.org\/10.1053\/j.gastro.2016.10.040","journal-title":"Gastroenterology"},{"key":"337_CR9","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1471-2156-14-6","volume":"14","author":"EL Chin","year":"2013","unstructured":"Chin EL, da Silva C, Hegde M (2013) Assessment of clinical analytical sensitivity and specificity of next-generation sequencing for detection of simple and complex mutations. 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