The Icelandic population offers several advantages for studying the genetic epidemiology and associated cancer risks of LS 15. Recently, a collaborative effort was undertaken to reclassify MMR variants in the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database ( ) 14. Furthermore, numerous reported variants of uncertain clinical significance (VUS) complicate genetic counseling. MLH1-hm can be assessed directly or inferred by the presence of a somatic BRAF V600E mutation 13.ĭue to the low frequency of individual LS mutations and heterogeneity in phenotypic expression, it has proven difficult to accurately establish population-based prevalences and to assess the cancer penetrance of LS gene mutations. Several groups in Europe and the United States have recommended universal screening of CRC 9, 10, 11, 12 using MSI testing or immunohistochemistry for the MMR proteins to identify potential LS cases. Furthermore, double somatic mismatch repair (MMR) mutations may explain up to 67% of dMMR CRC cases without LS or MLH1-hm 8. About 15% of CRC exhibit dMMR 5 with 2–3% caused by germline mutations in the MLH1, MSH2, MSH6, PMS2 or EPCAM genes 6 while 12% of CRC cases have somatic inactivation of MLH1 via promoter hypermethylation ( MLH1-hm) 7. Microsatellite instability (MSI) and mismatch repair deficiency (dMMR) are hallmarks of LS-related CRC. LS prevalence has never been determined across an entire nation. LS is also associated with increased lifetime risk of several other cancer types including endometrial and ovarian cancer 3, 4. The estimated population frequency is 1:370 to 1:2,000 in Western populations 1, 2. Lynch syndrome (LS) is the most common inherited cause of colorectal cancer (CRC). We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. The population prevalence of Lynch syndrome is 0.442%. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. We use colorectal cancer samples from 1,182 patients diagnosed between 2000–2009. 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. Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Nature Communications volume 8, Article number: 14755 ( 2017) Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2
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