{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:52:11Z","timestamp":1785891131663,"version":"3.56.0"},"reference-count":46,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008871","name":"Yunnan Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["202101AT070234"],"award-info":[{"award-number":["202101AT070234"]}],"id":[{"id":"10.13039\/501100008871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019413","name":"Yunnan Provincial Department of Education Science Research Fund Project","doi-asserted-by":"publisher","award":["2024Y227"],"award-info":[{"award-number":["2024Y227"]}],"id":[{"id":"10.13039\/501100019413","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Gene"],"published-print":{"date-parts":[[2026,10]]},"DOI":"10.1016\/j.gene.2026.150268","type":"journal-article","created":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T17:45:48Z","timestamp":1781459148000},"page":"150268","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"C","title":["Identification and pathogenicity validation of a novel MLH1 frameshift mutation in Lynch syndrome pedigree"],"prefix":"10.1016","volume":"1007","author":[{"given":"Dayang","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3056-9029","authenticated-orcid":false,"given":"Zhu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"5","key":"10.1016\/j.gene.2026.150268_b0010","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.gim.2022.01.014","article-title":"Worldwide prevalence of Lynch syndrome in patients with colorectal cancer: Systematic review and meta-analysis","volume":"24","author":"Abu-Ghazaleh","year":"2022","journal-title":"Genet. Med."},{"issue":"2","key":"10.1016\/j.gene.2026.150268_b0015","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s10689-018-00117-1","article-title":"Recent advances in Lynch syndrome. [J]","volume":"18","author":"Biller","year":"2019","journal-title":"Fam. Cancer"},{"issue":"7","key":"10.1016\/j.gene.2026.150268_b0160","doi-asserted-by":"crossref","DOI":"10.1053\/j.gastro.2010.04.024","article-title":"Report from the Jerusalem workshop on Lynch syndrome-hereditary nonpolyposis colorectal cancer. [J]","volume":"138","author":"Boland","year":"2010","journal-title":"Gastroenterology"},{"issue":"7","key":"10.1016\/j.gene.2026.150268_b0150","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.autrev.2016.03.005","article-title":"Vascular hypothesis revisited: Role of stimulating antibodies against angiotensin and endothelin receptors in the pathogenesis of systemic sclerosis. [J]","volume":"15","author":"Cabral-Marques","year":"2016","journal-title":"Autoimmun. Rev."},{"issue":"3","key":"10.1016\/j.gene.2026.150268_b0190","doi-asserted-by":"crossref","first-page":"e34","DOI":"10.1136\/jmg.2003.013714","article-title":"A founder MLH1 mutation in families from the districts of Modena and Reggio-Emilia in northern Italy with hereditary non-polyposis colorectal cancer associated with protein elongation and instability. [J]","volume":"41","author":"Caluseriu","year":"2004","journal-title":"J. Med. Genet."},{"key":"10.1016\/j.gene.2026.150268_b0050","doi-asserted-by":"crossref","unstructured":"CANCER GENOME ATLAS N. Comprehensive molecular characterization of human colon and rectal cancer. [J]. Nature. 2012, 487(7407): 330-337.","DOI":"10.1038\/nature11252"},{"issue":"1","key":"10.1016\/j.gene.2026.150268_b0185","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13000-017-0613-8","article-title":"Molecular genetics of microsatellite-unstable colorectal cancer for pathologists. [J]","volume":"12","author":"Chen","year":"2017","journal-title":"Diagn. Pathol."},{"key":"10.1016\/j.gene.2026.150268_b0195","doi-asserted-by":"crossref","unstructured":"COX V L, SAEED BAMASHMOS A A, FOO W C, et al. Lynch Syndrome: Genomics Update and Imaging Review. [J]. Radiographics. 2018, 38(2): 483-499.","DOI":"10.1148\/rg.2018170075"},{"issue":"10207","key":"10.1016\/j.gene.2026.150268_b0025","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1016\/S0140-6736(19)32319-0","article-title":"Colorectal cancer. [J]","volume":"394","author":"Dekker","year":"2019","journal-title":"Lancet"},{"issue":"1","key":"10.1016\/j.gene.2026.150268_b0125","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N","article-title":"Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. [J]","volume":"15","author":"den Dunnen","year":"2000","journal-title":"Hum. Mutat."},{"issue":"7","key":"10.1016\/j.gene.2026.150268_b0020","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1038\/s41436-018-0372-2","article-title":"A functional assay-based procedure to classify mismatch repair gene variants in Lynch syndrome. [J]","volume":"21","author":"Drost","year":"2019","journal-title":"Genet. Med."},{"issue":"10","key":"10.1016\/j.gene.2026.150268_b0115","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1093\/annonc\/mdv278","article-title":"BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance. [J]","volume":"26","author":"Eccles","year":"2015","journal-title":"Ann. Oncol."},{"issue":"4","key":"10.1016\/j.gene.2026.150268_b0035","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.cgh.2010.10.033","article-title":"Rapid development of colorectal neoplasia in patients with Lynch syndrome. [J]","volume":"9","author":"Edelstein","year":"2011","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"10.1016\/j.gene.2026.150268_b0165","doi-asserted-by":"crossref","unstructured":"EVALUATION OF GENOMIC APPLICATIONS IN P, PREVENTION WORKING G. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. [J]. Genet Med. 2009, 11(1): 35-41.","DOI":"10.1097\/GIM.0b013e31818fa2ff"},{"issue":"4","key":"10.1016\/j.gene.2026.150268_b0230","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1053\/j.gastro.2021.06.073","article-title":"Recurrent frameshift neoantigen vaccine elicits protective immunity with reduced tumor burden and improved overall survival in a lynch syndrome mouse model. [J]","volume":"161","author":"Gebert","year":"2021","journal-title":"Gastroenterology"},{"issue":"1","key":"10.1016\/j.gene.2026.150268_b0070","first-page":"64","article-title":"C A-C A. Consensus on clinical diagnosis, treatment and pedigree management of hereditary colorectal cancer in China. [J]","volume":"40","author":"Genetics group of the committee of colorectal cancer,","year":"2018","journal-title":"Zhonghua Zhong Liu Za Zhi"},{"issue":"1","key":"10.1016\/j.gene.2026.150268_b0200","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.ccell.2020.11.004","article-title":"MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway. [J]","volume":"39","author":"Guan","year":"2021","journal-title":"Cancer Cell"},{"key":"10.1016\/j.gene.2026.150268_b0145","unstructured":"GUPTA S, PROVENZALE D, LLOR X, et al. NCCN Guidelines Insights: Genetic\/Familial High-Risk Assessment: Colorectal, Version 2.2019. [J]. J Natl Compr Canc Netw. 2019, 17(9): 1032-1041."},{"issue":"8","key":"10.1016\/j.gene.2026.150268_b0210","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1093\/nar\/gkl1166","article-title":"Nuclear localization of human DNA mismatch repair protein exonuclease 1 (hEXO1). [J]","volume":"35","author":"Knudsen","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.gene.2026.150268_b0180","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1146\/annurev-genet-112414-054722","article-title":"Eukaryotic mismatch repair in relation to DNA replication. [J]","volume":"49","author":"Kunkel","year":"2015","journal-title":"Annu. Rev. Genet."},{"issue":"4","key":"10.1016\/j.gene.2026.150268_b0155","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1200\/JCO.18.00283","article-title":"Microsatellite instability is associated with the presence of lynch syndrome pan-cancer","volume":"37","author":"Latham","year":"2019","journal-title":"J. Clin. Oncol."},{"issue":"4","key":"10.1016\/j.gene.2026.150268_b0085","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1002\/humu.9417","article-title":"Distinct patterns of germ-line deletions in MLH1 and MSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC). [J]","volume":"27","author":"Li","year":"2006","journal-title":"Hum. Mutat."},{"issue":"6","key":"10.1016\/j.gene.2026.150268_b0135","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0304141","article-title":"Functional analysis of MMR gene VUS from potential Lynch syndrome patients. [J]","volume":"19","author":"Mahdouani","year":"2024","journal-title":"PLoS One"},{"issue":"4","key":"10.1016\/j.gene.2026.150268_b0220","doi-asserted-by":"crossref","DOI":"10.3390\/cancers15041022","article-title":"Challenges and therapeutic opportunities in the dMMR\/MSI-H colorectal cancer landscape [J]","volume":"15","author":"Mulet-Margalef","year":"2023","journal-title":"Cancers (Basel)"},{"issue":"8","key":"10.1016\/j.gene.2026.150268_b0055","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/s11912-021-01085-z","article-title":"Immunology of Lynch syndrome. [J]","volume":"23","author":"Pastor","year":"2021","journal-title":"Curr. Oncol. Rep."},{"issue":"7","key":"10.1016\/j.gene.2026.150268_b0095","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1093\/hmg\/10.7.735","article-title":"Deficient DNA mismatch repair: a common etiologic factor for colon cancer. [J]","volume":"10","author":"Peltomaki","year":"2001","journal-title":"Hum. Mol. Genet."},{"issue":"4\u20135","key":"10.1016\/j.gene.2026.150268_b0100","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1155\/2004\/305058","article-title":"Mutations associated with HNPCC predisposition \u2013 Update of ICG-HNPCC\/INSiGHT mutation database. [J]","volume":"20","author":"Peltomaki","year":"2004","journal-title":"Dis. Markers"},{"issue":"5","key":"10.1016\/j.gene.2026.150268_b0175","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1053\/j.gastro.2022.08.058","article-title":"Lynch syndrome genetics and clinical implications. [J]","volume":"164","author":"Peltomaki","year":"2023","journal-title":"Gastroenterology"},{"issue":"3","key":"10.1016\/j.gene.2026.150268_b0170","first-page":"104","article-title":"Immunohistochemical evaluation of mismatch repair proteins in colorectal carcinoma: the AIFEG\/GIPAD proposal. [J]","volume":"108","author":"Remo","year":"2016","journal-title":"Pathologica"},{"issue":"3","key":"10.1016\/j.gene.2026.150268_b0040","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1136\/gut.50.3.382","article-title":"Proximal adenomas in hereditary non-polyposis colorectal cancer are prone to rapid malignant transformation","volume":"50","author":"Rijcken","year":"2002","journal-title":"[J]. Gut"},{"issue":"4","key":"10.1016\/j.gene.2026.150268_b0045","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1053\/j.gastro.2008.01.015","article-title":"Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. [J]","volume":"134","author":"Schwitalle","year":"2008","journal-title":"Gastroenterology"},{"key":"10.1016\/j.gene.2026.150268_b0060","doi-asserted-by":"crossref","unstructured":"SEPPALA T T, LATCHFORD A, NEGOI I, et al. European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender. [J]. Br J Surg. 2021, 108(5): 484-98.","DOI":"10.1002\/bjs.11902"},{"issue":"11","key":"10.1016\/j.gene.2026.150268_b0105","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1002\/humu.20903","article-title":"Assessing pathogenicity: Overview of results from the IARC unclassified genetic variants working group. [J]","volume":"29","author":"Tavtigian","year":"2008","journal-title":"Hum. Mutat."},{"issue":"6","key":"10.1016\/j.gene.2026.150268_b0080","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1002\/humu.10291","article-title":"Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: Identification of novel and recurrent deletions by MLPA. [J]","volume":"22","author":"Taylor","year":"2003","journal-title":"Hum. Mutat."},{"issue":"1","key":"10.1016\/j.gene.2026.150268_b0120","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/humu.22214","article-title":"Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions [J]","volume":"34","author":"Thompson","year":"2013","journal-title":"Hum. Mutat."},{"issue":"2","key":"10.1016\/j.gene.2026.150268_b0110","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/ng.2854","article-title":"Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. [J]","volume":"46","author":"Thompson","year":"2014","journal-title":"Nat. Genet."},{"issue":"4","key":"10.1016\/j.gene.2026.150268_b0005","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1093\/jnci\/djh034","article-title":"Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. [J]","volume":"96","author":"Umar","year":"2004","journal-title":"J. Natl Cancer Inst."},{"issue":"6","key":"10.1016\/j.gene.2026.150268_b0140","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/S0016-5085(99)70510-X","article-title":"New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. [J]","volume":"116","author":"Vasen","year":"1999","journal-title":"Gastroenterology"},{"issue":"2","key":"10.1016\/j.gene.2026.150268_b0030","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s12032-021-01454-5","article-title":"Prevalence of mutations in BRCA and MMR genes in patients affected with hereditary endometrial cancer","volume":"38","author":"Vietri","year":"2021","journal-title":"Med. Oncol."},{"issue":"1","key":"10.1016\/j.gene.2026.150268_b0090","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1002\/gcc.10094","article-title":"A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred. [J]","volume":"35","author":"Wagner","year":"2002","journal-title":"Genes Chromosomes Cancer"},{"issue":"1","key":"10.1016\/j.gene.2026.150268_b0130","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/humu.20654","article-title":"Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. [J]","volume":"29","author":"Wildeman","year":"2008","journal-title":"Hum. Mutat."},{"key":"10.1016\/j.gene.2026.150268_b0075","article-title":"Lynch syndrome: from detection to treatment. [J]. Front","volume":"13","author":"Williams","year":"2023","journal-title":"Oncol"},{"issue":"9","key":"10.1016\/j.gene.2026.150268_b0205","doi-asserted-by":"crossref","first-page":"3320","DOI":"10.1128\/MCB.23.9.3320-3328.2003","article-title":"Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha. [J]","volume":"23","author":"Wu","year":"2003","journal-title":"Mol. Cell Biol."},{"issue":"3","key":"10.1016\/j.gene.2026.150268_b0225","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1111\/cas.15650","article-title":"Pembrolizumab in Asian patients with microsatellite-instability-high\/mismatch-repair-deficient colorectal cancer. [J]","volume":"114","author":"Yoshino","year":"2023","journal-title":"Cancer Sci."},{"issue":"3","key":"10.1016\/j.gene.2026.150268_b0215","first-page":"379","article-title":"Role of deficient DNA mismatch repair status in patients with stage III colon cancer treated with FOLFOX adjuvant chemotherapy: A pooled analysis from 2 randomized clinical trials. [J]. JAMA","volume":"4","author":"Zaanan","year":"2018","journal-title":"Oncol"},{"issue":"3","key":"10.1016\/j.gene.2026.150268_b0065","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.critrevonc.2014.10.005","article-title":"Mismatch repair gone awry: Management of Lynch syndrome. [J]","volume":"93","author":"Zhang","year":"2015","journal-title":"Crit. Rev. Oncol. Hematol."}],"container-title":["Gene"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0378111926002787?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0378111926002787?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:23:43Z","timestamp":1785889423000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0378111926002787"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":46,"alternative-id":["S0378111926002787"],"URL":"https:\/\/doi.org\/10.1016\/j.gene.2026.150268","relation":{},"ISSN":["0378-1119"],"issn-type":[{"value":"0378-1119","type":"print"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Identification and pathogenicity validation of a novel MLH1 frameshift mutation in Lynch syndrome pedigree","name":"articletitle","label":"Article Title"},{"value":"Gene","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.gene.2026.150268","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Author(s). Published by Elsevier B.V.","name":"copyright","label":"Copyright"}],"article-number":"150268"}}