{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:37:56Z","timestamp":1786981076628,"version":"build-2736575974"},"reference-count":6,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T00:00:00Z","timestamp":1717718400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T00:00:00Z","timestamp":1717718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Research Council of Finland","doi-asserted-by":"crossref","award":["312041"],"award-info":[{"award-number":["312041"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002341","name":"Research Council of Finland","doi-asserted-by":"crossref","award":["312041"],"award-info":[{"award-number":["312041"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004012","name":"Jane and Aatos Erkko Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004012","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002341","name":"Research Council of Finland","doi-asserted-by":"crossref","award":["320149"],"award-info":[{"award-number":["320149"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"crossref"}]},{"name":"iCAN Digital Precision Cancer Medicine Flagship"},{"DOI":"10.13039\/501100010711","name":"Cancer Foundation Finland","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100010711","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007797","name":"University of Helsinki","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007797","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Familial Cancer"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Some 50% of Finnish Lynch Syndrome (LS) cases are caused by a founder variant in\n                    <jats:italic>MLH1<\/jats:italic>\n                    , in which the entire exon 16 has been lost due to an Alu-mediated recombination event. We piloted detecting the variant in FinnGen, a large genotyped cohort comprising approximately 10% of the current Finnish population, and validated the\n                    <jats:italic>MLH1<\/jats:italic>\n                    founder variant status of identified individuals residing in the Central Finland Biobank catchment area. A consensus sequence flanking the deletion was identified in whole genome sequences of six LS individuals with the founder variant. Genotype data of 212,196 individuals was queried for regional matches to the consensus sequence. Enrichment of cancer and age at cancer onset was compared between matching and non-matching individuals. Variant status was validated for a subset of the identified individuals using a polymerase chain reaction assay. Allelic matches in a chosen target region was detected in 348 individuals, with 89 having a cancer diagnosis (Bonferroni-adjusted p-value\u2009=\u20091), 20 a familial cancer history (p-adj.\u2009&lt;\u2009.001), with mean age of onset of cancer being 53.6\u00a0years (p-adj.\u2009=\u2009.002). Eighteen of potential variant carriers had been sampled by the Central Finland Biobank, of which four (22%) were validated as true variant carriers. The workflow we have employed identifies\n                    <jats:italic>MLH1<\/jats:italic>\n                    exon 16 deletion variant carriers from population-wide SNP genotyping data. An alternative design will be sought to limit false positive findings. Large genotyped cohorts provide a potential resource for identification and prevention of hereditary cancer.\n                  <\/jats:p>","DOI":"10.1007\/s10689-024-00400-4","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T05:01:46Z","timestamp":1717736506000},"page":"647-652","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Detection of a major Lynch Syndrome-causing MLH1 founder variant in a large-scale genotyped cohort"],"prefix":"10.1007","volume":"23","author":[{"given":"Lauri J.","family":"Sipil\u00e4","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mervi","family":"Aavikko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janne","family":"Ravantti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teijo","family":"Kuopio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Lahtinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"FinnGen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4ivi","family":"Peltom\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka-Pekka","family":"Mecklin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauri A.","family":"Aaltonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni T.","family":"Sepp\u00e4l\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,7]]},"reference":[{"key":"400_CR1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/s41436-019-0596-9","volume":"22","author":"M Dominguez-Valentin","year":"2020","unstructured":"Dominguez-Valentin M, Sampson JR, Sepp\u00e4l\u00e4 TT et al (2020) Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 22:15\u201325. https:\/\/doi.org\/10.1038\/s41436-019-0596-9","journal-title":"Genet Med"},{"key":"400_CR2","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s13053-023-00263-3","volume":"21","author":"P M\u00f8ller","year":"2023","unstructured":"M\u00f8ller P, Sepp\u00e4l\u00e4 TT, Ahadova A et al (2023) Dominantly inherited micro-satellite instable cancer\u2014the four Lynch syndromes\u2014an EHTG, PLSD position statement. Hered Cancer Clin Pract 21:19. https:\/\/doi.org\/10.1186\/s13053-023-00263-3","journal-title":"Hered Cancer Clin Pract"},{"key":"400_CR3","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1038\/nm1195-1203","volume":"1","author":"M Nystr\u00f6m-Lahti","year":"1995","unstructured":"Nystr\u00f6m-Lahti M, Kristo P, Nicolaides NC et al (1995) Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nat Med 1:1203\u20131206. https:\/\/doi.org\/10.1038\/nm1195-1203","journal-title":"Nat Med"},{"key":"400_CR4","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","volume":"613","author":"MI Kurki","year":"2023","unstructured":"Kurki MI, Karjalainen J, Palta P et al (2023) FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613:508\u2013518. https:\/\/doi.org\/10.1038\/s41586-022-05473-8","journal-title":"Nature"},{"key":"400_CR5","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1007\/s10689-013-9616-0","volume":"12","author":"JP Plazzer","year":"2013","unstructured":"Plazzer JP, Sijmons RH, Woods MO et al (2013) The InSiGHT database: utilizing 100 years of insights into Lynch Syndrome. Fam Cancer 12:175\u2013180. https:\/\/doi.org\/10.1007\/s10689-013-9616-0","journal-title":"Fam Cancer"},{"key":"400_CR6","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n214","author":"MN Weedon","year":"2021","unstructured":"Weedon MN, Jackson L, Harrison JW et al (2021) Use of SNP chips to detect rare pathogenic variants retrospective population based diagnostic evaluation. BMJ. https:\/\/doi.org\/10.1136\/bmj.n214","journal-title":"BMJ"}],"container-title":["Familial Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-024-00400-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10689-024-00400-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-024-00400-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,26]],"date-time":"2024-10-26T05:17:18Z","timestamp":1729919838000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10689-024-00400-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,7]]},"references-count":6,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["400"],"URL":"https:\/\/doi.org\/10.1007\/s10689-024-00400-4","relation":{},"ISSN":["1389-9600","1573-7292"],"issn-type":[{"value":"1389-9600","type":"print"},{"value":"1573-7292","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,7]]},"assertion":[{"value":"19 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 May 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 June 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"T.T.S. declares a consultation fee from Amgen Finland, Tillots Pharma and Nouscom. T.T.S is CEO and co-owner of Healthfund Finland and Clinical Advisory board member of LS Cancer Diag. P.P. is a Clinical Advisory board member of LS Cancer Diag. Other authors declare no conflicting interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"T.T.S. declares a consultation fee from Amgen Finland, Tillots Pharma and Nouscom. T.T.S is CEO and co-owner of Healthfund Finland and Clinical Advisory board member of LS Cancer Diag. P.P. is a Clinical Advisory board member of LS Cancer Diag. Other authors declare no conflicting interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Variant validation was conducted in collaboration with Central Finland Biobank, using tissue material stored in the biobank. An ethics approval for the RETURN project has been applied for and received from The Ethics Committee of the Wellbeing Services County of Pirkanmaa (R23004B, 9\/2023).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}