RT Journal Article SR Electronic T1 Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 579 OP 585 DO 10.1136/jmg.2010.077677 VO 47 IS 9 A1 Wenche Sjursen A1 Bjørn Ivar Haukanes A1 Eli Marie Grindedal A1 Harald Aarset A1 Astrid Stormorken A1 Lars F Engebretsen A1 Christoffer Jonsrud A1 Inga Bjørnevoll A1 Per Arne Andresen A1 Sarah Ariansen A1 Liss Anne S Lavik A1 Bodil Gilde A1 Inger Marie Bowitz-Lothe A1 Lovise Mæhle A1 Pål Møller YR 2010 UL http://jmg.bmj.com/content/47/9/579.abstract AB Background Reported prevalence, penetrance and expression of deleterious mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, may reflect differences in the clinical criteria used to select families for DNA testing. The authors have previously reported that clinical criteria are not sensitive enough to identify MMR mutation carriers among incident colorectal cancer cases.Objective To describe the sensitivity of the criteria when applied to families with a demonstrated MMR mutation.Methods Families with an aggregation of colorectal cancers were examined for deleterious MMR mutations according to the Mallorca guidelines. All families with a detected MMR mutation as of November 2009 were reclassified according to the Amsterdam and Bethesda criteria.Results Sixty-nine different DNA variants were identified in a total of 129 families. The original Amsterdam clinical criteria were met by 38%, 12%, 78% and 25% of families with mutations in MSH2, MSH6, MLH1 and PMS2, respectively. Corresponding numbers for the revised Amsterdam criteria were 62%, 48%, 87% and 38%. Similarly, each of the four clinical Bethesda criteria had low sensitivity for identifying MSH6 or PMS2 mutations.Conclusion Amsterdam criteria and each of the Bethesda criteria were inadequate for identifying MSH6 mutation-carrying kindreds. MSH6 mutations may be more common than currently assumed, and the penetrance/expression of MSH6 mutations, as derived from families meeting current clinical criteria, may be misleading. To increase detection rate of MMR mutation carriers, all cancers in the Lynch syndrome tumour spectrum should be subjected to immunohistochemical analysis and/or analysis for microsatellite instability.