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Identification of these patients are critical as they are at substantially increased risk of developing multiple primary tumors, mainly colorectal and endometrial cancer (<jats:styled-content style=\"fixed-case\">EC<\/jats:styled-content>), occurring at a young age. This demonstrates the need to develop new and\/or more thorough mutation detection approaches. Next\u2010generation sequencing (<jats:styled-content style=\"fixed-case\">NGS<\/jats:styled-content>) was used to screen 22 genes involved in the <jats:styled-content style=\"fixed-case\">DNA MMR<\/jats:styled-content> pathway in constitutional <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> from 14 <jats:styled-content style=\"fixed-case\">HNPCC<\/jats:styled-content> and 12 sporadic <jats:styled-content style=\"fixed-case\">EC<\/jats:styled-content> patients, plus 2 positive controls. Several softwares were used for analysis and functional annotation. We identified 5 exonic indel variants, 42 exonic nonsynonymous single\u2010nucleotide variants (<jats:styled-content style=\"fixed-case\">SNV<\/jats:styled-content>s) and 1 intronic variant of significance. Three of these variants were class 5 (pathogenic) or class 4 (likely pathogenic), 5 were class 3 (uncertain clinical relevance) and 40 were classified as variants of unknown clinical significance. In conclusion, we have identified two <jats:styled-content style=\"fixed-case\">LS<\/jats:styled-content> families from the sporadic <jats:styled-content style=\"fixed-case\">EC<\/jats:styled-content> patients, one without a family history of cancer, supporting the notion for universal <jats:styled-content style=\"fixed-case\">MMR<\/jats:styled-content> screening of <jats:styled-content style=\"fixed-case\">EC<\/jats:styled-content> patients. In addition, we have detected three novel class 3 variants in <jats:styled-content style=\"fixed-case\">EC<\/jats:styled-content> cases. We have, in addition discovered a polygenic interaction which is the most likely cause of cancer development in a <jats:styled-content style=\"fixed-case\">HNPCC<\/jats:styled-content> patient that could explain previous inconsistent results reported on an intronic <jats:italic><jats:styled-content style=\"fixed-case\">EXO<\/jats:styled-content>1<\/jats:italic> variant.<\/jats:p>","DOI":"10.1002\/cam4.628","type":"journal-article","created":{"date-parts":[[2016,1,26]],"date-time":"2016-01-26T01:13:00Z","timestamp":1453770780000},"page":"929-941","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Targeted next\u2010generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families"],"prefix":"10.1002","volume":"5","author":[{"given":"Bente A.","family":"Talseth\u2010Palmer","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy Faculty of Health and Medicine University of Newcastle  Newcastle New South Wales Australia"},{"name":"Centre for Information\u2010Based Medicine Hunter Medical Research Institute  Newcastle New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis C.","family":"Bauer","sequence":"additional","affiliation":[{"name":"CSIRO Digital Productivity  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenche","family":"Sjursen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Children's and Women's Health Norwegian University of Science and Technology  Trondheim Norway"},{"name":"Department of Pathology and Medical Genetics St Olavs University Hospital  Trondheim Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany J.","family":"Evans","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy Faculty of Health and Medicine University of Newcastle  Newcastle New South Wales Australia"},{"name":"Centre for Information\u2010Based Medicine Hunter Medical Research Institute  Newcastle New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"McPhillips","sequence":"additional","affiliation":[{"name":"Hunter Area Pathology Service Pathology North Hunter New England Area Health  Newcastle New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Proietto","sequence":"additional","affiliation":[{"name":"Hunter Centre for Gynaecological Cancer Hunter New England Area Health  Newcastle New South Wales Australia"},{"name":"School of Medicine and Public Health Faculty of Health and Medicine University of Newcastle  New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Otton","sequence":"additional","affiliation":[{"name":"Hunter Centre for Gynaecological Cancer Hunter New England Area Health  Newcastle New South Wales Australia"},{"name":"School of Medicine and Public Health Faculty of Health and Medicine University of Newcastle  New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan D.","family":"Spigelman","sequence":"additional","affiliation":[{"name":"Hunter Family Cancer Service Hunter New England Area Health  Newcastle New South Wales Australia"},{"name":"St Vincent's Hospital Clinical School University of NSW and Hospital Cancer Genetics Clinic The Kinghorn Cancer Centre  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney J.","family":"Scott","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy Faculty of Health and Medicine University of Newcastle  Newcastle New South Wales Australia"},{"name":"Centre for Information\u2010Based Medicine Hunter Medical Research Institute  Newcastle New South Wales Australia"},{"name":"Hunter Area Pathology Service Pathology North Hunter New England Area Health  Newcastle New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,1,25]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(00)70168-5"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.20006"},{"key":"e_1_2_7_4_1","first-page":"9","article-title":"Molecular genetics of colorectal cancer","volume":"27","author":"Bogaert J.","year":"2014","journal-title":"Ann. 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