{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:37:45Z","timestamp":1792456665894,"version":"4.5.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"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"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Lynch syndrome, the most common hereditary cancer syndrome, is caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. Identifying complex or structural MMR gene pathogenic variants can be challenging with short-read sequencing resulting in patients with unexplained MMR-deficient tumours. In this study, we report multiple members of a family who developed MSH2-deficient tumours where clinical multi-gene panel testing of the DNA MMR genes using short-read sequencing did not find a germline pathogenic variant. Oxford Nanopore Technologies adaptive sampling (ONT-AS) long-read sequencing, targeting 104 hereditary cancer genes, identified a shared\u2009~\u20093.2\u00a0kb SINE-VNTR-Alu (SVA) family F retrotransposon insertion within exon 12 of\n                    <jats:italic>MSH2<\/jats:italic>\n                    in both the proband and her father. Segregation of this\n                    <jats:italic>MSH2<\/jats:italic>\n                    SVA insertion by targeted PCR confirmed three additional family members as carriers, including a paternal uncle with three colorectal cancers and an MSH2-deficient sebaceous adenoma. Three of the five heterozygous carriers were cancer affected with at least one MSH2-deficient tumour each. This study demonstrates that long-read sequencing can identify structural variants that are missed by current short-read sequencing multi-gene panel testing, improving the diagnosis of Lynch syndrome. These findings support incorporating long-read sequencing into routine diagnostic workflows for patients with suspected Lynch syndrome following a negative germline test.\n                  <\/jats:p>","DOI":"10.1007\/s10689-026-00588-7","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T12:10:15Z","timestamp":1783599015000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lynch syndrome caused by a pathogenic SINE-VNTR-Alu (SVA) insertion in MSH2 gene identified by long-read DNA sequencing"],"prefix":"10.1007","volume":"25","author":[{"given":"Jihoon E.","family":"Joo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid","family":"Mahmood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Clendenning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Georgeson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romy","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Como","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard J.","family":"Pope","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Batinovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Diepenhorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni","family":"Rice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Rosty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Jenkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Finlay A.","family":"Macrae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M.","family":"Winship","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilda","family":"High","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":[[2026,7,9]]},"reference":[{"issue":"3","key":"588_CR1","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1158\/1055-9965.EPI-16-0693","volume":"26","author":"AK Win","year":"2017","unstructured":"Win AK et al (2017) Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev 26(3):404\u2013412","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"588_CR2","first-page":"183","volume":"7","author":"DD Buchanan","year":"2014","unstructured":"Buchanan DD et al (2014) Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome). Appl Clin Genet 7:183\u2013193","journal-title":"Appl Clin Genet"},{"issue":"1","key":"588_CR3","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1186\/s12967-023-04143-1","volume":"21","author":"R Walker","year":"2023","unstructured":"Walker R et al (2023) A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome. J Transl Med 21(1):282","journal-title":"J Transl Med"},{"issue":"5","key":"588_CR4","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1007\/s00439-004-1176-9","volume":"115","author":"M Kloor","year":"2004","unstructured":"Kloor M et al (2004) A large MSH2 Alu insertion mutation causes HNPCC in a German kindred. Hum Genet 115(5):432\u2013438","journal-title":"Hum Genet"},{"issue":"11","key":"588_CR5","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1038\/s41431-018-0207-2","volume":"26","author":"S Baert-Desurmont","year":"2018","unstructured":"Baert-Desurmont S et al (2018) Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes. Eur J Hum Genet 26(11):1597\u20131602","journal-title":"Eur J Hum Genet"},{"issue":"7","key":"588_CR6","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1002\/humu.22092","volume":"33","author":"HM van der Klift","year":"2012","unstructured":"van der Klift HM et al (2012) Insertion of an SVA element, a nonautonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome. Hum Mutat 33(7):1051\u20131055","journal-title":"Hum Mutat"},{"issue":"8","key":"588_CR7","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1002\/gcc.22950","volume":"60","author":"C Yang","year":"2021","unstructured":"Yang C et al (2021) Insertion of an SVA element in MSH2 as a novel cause of Lynch syndrome. Genes Chromosomes Cancer 60(8):571\u2013576","journal-title":"Genes Chromosomes Cancer"},{"issue":"2","key":"588_CR8","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1007\/s10689-011-9427-0","volume":"10","author":"M Clendenning","year":"2011","unstructured":"Clendenning M et al (2011) Mutation deep within an intron of MSH2 causes Lynch syndrome. Fam Cancer 10(2):297\u2013301","journal-title":"Fam Cancer"},{"issue":"6","key":"588_CR9","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1053\/j.gastro.2022.08.041","volume":"163","author":"I Te Paske","year":"2022","unstructured":"Te Paske I et al (2022) Noncoding aberrations in mismatch repair genes underlie a substantial part of the missing heritability in Lynch syndrome. Gastroenterology 163(6):1691\u20131694","journal-title":"Gastroenterology"},{"issue":"1","key":"588_CR10","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s13053-025-00324-9","volume":"23","author":"W Sjursen","year":"2025","unstructured":"Sjursen W et al (2025) Lynch syndrome caused by SINE-VNTR-Alu-F retrotransposon insert in MSH6 confirmed after 20 years of testing: a case report and literature review. Hered Cancer Clin Pract 23(1):22","journal-title":"Hered Cancer Clin Pract"},{"issue":"5","key":"588_CR11","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/s41431-023-01494-7","volume":"32","author":"PM Bjornstad","year":"2024","unstructured":"Bjornstad PM et al (2024) A 39 kb structural variant causing Lynch Syndrome detected by optical genome mapping and nanopore sequencing. Eur J Hum Genet 32(5):513\u2013520","journal-title":"Eur J Hum Genet"},{"issue":"4","key":"588_CR12","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1038\/s41431-020-00779-5","volume":"29","author":"G Yamamoto","year":"2021","unstructured":"Yamamoto G et al (2021) SVA retrotransposon insertion in exon of MMR genes results in aberrant RNA splicing and causes Lynch syndrome. Eur J Hum Genet 29(4):680\u2013686","journal-title":"Eur J Hum Genet"},{"key":"588_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2024.102266","volume":"52","author":"R Walker","year":"2025","unstructured":"Walker R et al (2025) Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications. Transl Oncol 52:102266","journal-title":"Transl Oncol"},{"issue":"2","key":"588_CR14","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.jmoldx.2022.10.003","volume":"25","author":"R Walker","year":"2023","unstructured":"Walker R et al (2023) Evaluating multiple next-generation sequencing\u2013derived tumor features to accurately predict DNA mismatch repair status. J Mol Diagn 25(2):94\u2013109","journal-title":"J Mol Diagn"},{"issue":"1","key":"588_CR15","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1186\/s12967-023-04143-1","volume":"21","author":"R Walker","year":"2023","unstructured":"Walker R et al (2023) A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome. J Transl Med 21(1):282","journal-title":"J Transl Med"},{"issue":"6","key":"588_CR16","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41576-018-0003-4","volume":"19","author":"FJ Sedlazeck","year":"2018","unstructured":"Sedlazeck FJ et al (2018) Piercing the dark matter: bioinformatics of long-range sequencing and mapping. Nat Rev Genet 19(6):329\u2013346","journal-title":"Nat Rev Genet"},{"issue":"1","key":"588_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24041-8","volume":"12","author":"C Chu","year":"2021","unstructured":"Chu C et al (2021) Comprehensive identification of transposable element insertions using multiple sequencing technologies. Nat Commun 12(1):3836","journal-title":"Nat Commun"},{"issue":"6196","key":"588_CR18","doi-asserted-by":"publisher","first-page":"1251343","DOI":"10.1126\/science.1251343","volume":"345","author":"JMC Tubio","year":"2014","unstructured":"Tubio JMC et al (2014) Mobile DNA in cancer Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 345(6196):1251343","journal-title":"Science"},{"issue":"3","key":"588_CR19","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.jmoldx.2020.12.003","volume":"23","author":"BJ Pope","year":"2021","unstructured":"Pope BJ et al (2021) Germline and tumor sequencing as a diagnostic tool to resolve suspected Lynch syndrome. J Mol Diagn 23(3):358\u2013371","journal-title":"J Mol Diagn"},{"issue":"12","key":"588_CR20","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1038\/gim.2018.47","volume":"20","author":"J Leclerc","year":"2018","unstructured":"Leclerc J et al (2018) Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation. Genet Med 20(12):1589\u20131599","journal-title":"Genet Med"},{"issue":"12","key":"588_CR21","doi-asserted-by":"publisher","first-page":"e1523","DOI":"10.1002\/mgg3.1523","volume":"8","author":"Y Li","year":"2020","unstructured":"Li Y et al (2020) Insertion of an Alu-like element in MLH1 intron 7 as a novel cause of Lynch syndrome. Mol Genet Genomic Med 8(12):e1523","journal-title":"Mol Genet Genomic Med"},{"key":"588_CR22","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.cancergen.2017.08.002","volume":"216-217","author":"Y Qian","year":"2017","unstructured":"Qian Y et al (2017) Identification of pathogenic retrotransposon insertions in cancer predisposition genes. Cancer Genet 216\u2013217:159\u2013169","journal-title":"Cancer Genet"},{"issue":"8","key":"588_CR23","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1136\/jmg-2022-108931","volume":"60","author":"V Schwenk","year":"2023","unstructured":"Schwenk V et al (2023) Transcript capture and ultradeep long-read RNA sequencing (CAPLRseq) to diagnose HNPCC\/Lynch syndrome. J Med Genet 60(8):747\u2013759","journal-title":"J Med Genet"},{"issue":"6","key":"588_CR24","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1002\/humu.23725","volume":"40","author":"J Solassol","year":"2019","unstructured":"Solassol J et al (2019) Alu element insertion in the MLH1 exon 6 coding sequence as a mutation predisposing to Lynch syndrome. Hum Mutat 40(6):716\u2013720","journal-title":"Hum Mutat"}],"container-title":["Familial Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-026-00588-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10689-026-00588-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-026-00588-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T12:10:16Z","timestamp":1783599016000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10689-026-00588-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":24,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["588"],"URL":"https:\/\/doi.org\/10.1007\/s10689-026-00588-7","relation":{},"ISSN":["1573-7292"],"issn-type":[{"value":"1573-7292","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]},"assertion":[{"value":"7 May 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Steven Batinovic is an employee of Oxford Nanopore Technologies.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"75"}}