{"doi":"10.1038/ncomms14755","title":"Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2","abstract":"<jats:title>Abstract</jats:title><jats:p>Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000–2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting<jats:italic>MLH1</jats:italic>and three mutations in<jats:italic>MSH6</jats:italic>and<jats:italic>PMS2</jats:italic>that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in<jats:italic>MSH6</jats:italic>and<jats:italic>PMS2</jats:italic>prevail in Iceland unlike most other populations.</jats:p>","journal":"Nature Communications","year":2017,"id":637959,"datarank":0.7242470605953454,"base_score":4.8283137373023015,"endowment":4.8283137373023015,"self_citation_contribution":0.7242470605953454,"citation_network_contribution":0.0,"self_endowment_contribution":0.7242470605953454,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":124,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":19,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":7028,"name":"Thorunn Rafnar","orcid":null,"position":1,"is_corresponding":false},{"id":380164,"name":"Wendy L. Frankel","orcid":"0000-0003-1658-1009","position":2,"is_corresponding":false},{"id":1656739,"name":"Sylvia Einarsdottir","orcid":null,"position":3,"is_corresponding":false},{"id":1656742,"name":"Asgeir Sigurdsson","orcid":null,"position":4,"is_corresponding":false},{"id":175602,"name":"Heather Hampel","orcid":null,"position":5,"is_corresponding":false},{"id":1656745,"name":"Petur Snaebjornsson","orcid":null,"position":6,"is_corresponding":false},{"id":7033,"name":"Gisli Masson","orcid":null,"position":7,"is_corresponding":false},{"id":345252,"name":"Daniel Weng","orcid":"0000-0003-3903-9407","position":8,"is_corresponding":false},{"id":1656748,"name":"Reynir Arngrimsson","orcid":null,"position":9,"is_corresponding":false},{"id":7013,"name":"Birte Kehr","orcid":"0000-0002-3417-7504","position":10,"is_corresponding":false},{"id":1656749,"name":"Ahmet Yilmaz","orcid":null,"position":11,"is_corresponding":false},{"id":1656750,"name":"Stefan Haraldsson","orcid":null,"position":12,"is_corresponding":false},{"id":7012,"name":"Patrick Sulem","orcid":"0000-0001-7123-6123","position":13,"is_corresponding":false},{"id":1656752,"name":"Tryggvi Stefansson","orcid":null,"position":14,"is_corresponding":false},{"id":274565,"name":"Peter G. Shields","orcid":"0000-0002-7404-217X","position":15,"is_corresponding":false},{"id":1656754,"name":"Fridbjorn Sigurdsson","orcid":null,"position":16,"is_corresponding":false},{"id":1413884,"name":"Tanios Bekaii-Saab","orcid":null,"position":17,"is_corresponding":false},{"id":1656757,"name":"Pall H. Moller","orcid":null,"position":18,"is_corresponding":false},{"id":1656758,"name":"Margret Steinarsdottir","orcid":null,"position":19,"is_corresponding":false},{"id":1656759,"name":"Kristin Alexiusdottir","orcid":null,"position":20,"is_corresponding":false},{"id":1656760,"name":"Megan Hitchins","orcid":null,"position":21,"is_corresponding":false},{"id":255748,"name":"Colin C. Pritchard","orcid":"0000-0002-2461-1557","position":22,"is_corresponding":false},{"id":4794,"name":"Albert de la Chapelle","orcid":"0000-0001-9345-9248","position":23,"is_corresponding":false},{"id":13619,"name":"Jon G. Jonasson","orcid":null,"position":24,"is_corresponding":false},{"id":62905,"name":"Richard M. Goldberg","orcid":"0000-0003-0308-8223","position":25,"is_corresponding":false},{"id":5356,"name":"Kari Stefansson","orcid":null,"position":26,"is_corresponding":false},{"id":577437,"name":"Sigurdís Haraldsdóttir","orcid":"0000-0002-5050-3699","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2","abstract":"<jats:title>Abstract</jats:title><jats:p>Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000–2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting<jats:italic>MLH1</jats:italic>and three mutations in<jats:italic>MSH6</jats:italic>and<jats:italic>PMS2</jats:italic>that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in<jats:italic>MSH6</jats:italic>and<jats:italic>PMS2</jats:italic>prevail in Iceland unlike most other populations.</jats:p>","is_dataset_classified":null,"base_score":4.8283137373023015,"endowment":4.8283137373023015,"datacite_reuse_total":19,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"28466842","pmcid":"PMC5418568","openalex_id":"https://openalex.org/W2610764386","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"P30 CA016058","title":null},{"funder_name":"National Institutes of Health","grant_id":"3P30CA016058-15S1","title":"CORE--HORMONE RECEPTOR LABORATORY"}],"total_grants":2,"fwci":6.5329,"citation_percentile":0.97728771,"influential_citations":0,"citation_trend":[{"year":2017,"count":3},{"year":2018,"count":11},{"year":2019,"count":12},{"year":2020,"count":12},{"year":2021,"count":19},{"year":2022,"count":16},{"year":2023,"count":26},{"year":2024,"count":13},{"year":2025,"count":8},{"year":2026,"count":3}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/ncomms14755.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/ncomms14755.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/ncomms14755","host_type":"publisher"},{"url":"http://www.nature.com/doifinder/10.1038/ncomms14755","host_type":"publisher"},{"url":"https://doi.org/10.1038/ncomms14755","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/28466842","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5418568","host_type":"repository"},{"url":"https://researchrepository.wvu.edu/faculty_publications/1699","host_type":"repository"},{"url":"https://doaj.org/article/892427e1e8434dbab0cf538d0c78f168","host_type":"repository"},{"url":"https://hdl.handle.net/20.500.11815/374","host_type":"repository"},{"url":"https://vbn.aau.dk/da/publications/0e9cc76b-ac3a-4315-8f61-557fd51bf3d4","host_type":"repository"},{"url":"http://hdl.handle.net/2336/620229","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC5418568","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC5418568?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1038/ncomms14755","host_type":""},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418568/pdf/ncomms14755.pdf","host_type":""},{"url":"https://dx.doi.org/10.1038/ncomms14755","host_type":""}],"fields_of_study":["Genetic factors in colorectal cancer","Colorectal Cancer Screening and Detection","Cancer Genomics and Diagnostics","0301 basic medicine","03 medical and health sciences","0303 health sciences","Adult","Aged","Aged, 80 and over","Base Pair Mismatch","Colorectal Neoplasms, Hereditary Nonpolyposis","DNA-Binding Proteins","Female","Founder Effect","Genetic Predisposition to Disease","Germ-Line Mutation","Humans","Iceland","Male","Middle Aged","Mismatch Repair Endonuclease PMS2","Prevalence"],"mesh_terms":["Mismatch Repair Endonuclease PMS2","Adult","Aged","Aged, 80 and over","Colorectal Neoplasms, Hereditary Nonpolyposis","DNA-Binding Proteins","Female","Humans","Iceland","Male","Middle Aged","Prevalence","Germ-Line Mutation","Founder Effect","Genetic Predisposition to Disease","Base Pair Mismatch"],"keywords":["Lynch syndrome","PMS2","MSH6","MLH1","Germline mutation","Genetics","Population","Biology","MSH2","Founder effect","Oncology","Cancer","Colorectal cancer","Medicine","Mutation","DNA mismatch repair","Internal medicine","Gene","Haplotype","Adult","Male","Erfðagreining","Base Pair Mismatch","Science","Iceland","Article","Cancer epidemiology","Krabbameinsrannsóknir","Cancer genomics","Journal Article","Prevalence","Humans","Genetic Predisposition to Disease","Cancer genetics","Germ-Line Mutation","Krabbamein","Aged","Mismatch Repair Endonuclease PMS2","Aged, 80 and over","Q","Arfgengi","Middle Aged","Colorectal Neoplasms, Hereditary Nonpolyposis","DNA-Binding Proteins","Female"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":16,"sdg_label":"16. Peace & justice"},{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.22598648.v1","title":"Additional file 2 of Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.22598648","title":"Additional file 2 of Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.22598657.v1","title":"Additional file 5 of Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.22598657","title":"Additional file 5 of Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25107728.v1","title":"Additional file 1 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.25107728","title":"Additional file 1 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"JournalArticle"},{"doi":"10.6084/m9.figshare.26673933.v1","title":"Additional file 3 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.26673942","title":"Additional file 6 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.25107892.v1","title":"Additional file 2 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.26673936","title":"Additional file 4 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.26673939","title":"Additional file 5 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.26673942.v1","title":"Additional file 6 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.26673939.v1","title":"Additional file 5 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.25107892","title":"Additional file 2 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.26673933","title":"Additional file 3 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.26673936.v1","title":"Additional file 4 of Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.22598651","title":"Additional file 3 of Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.22598651.v1","title":"Additional file 3 of Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.22598654.v1","title":"Additional file 4 of Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome","publisher":"figshare","resource_type":"Dataset"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T19:48:42.563927Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}