Detection of Mutations by Screening Hereditary Nonpolyposis Colon Cancer Families from Denmark and Sweden.

Hereditary nonpolyposis colon cancer (HNPCC) and Lynch syndrome (LS) are characterized by defects in the mismatch repair (MMR) system, which protects the integrity of the genome. Pathogenic variants in four MMR genes (, , , and ) are responsible for LS, an autosomal, dominant hereditary disease that occurs with a frequency of 2-5% among all colorectal cancer cases. It has been estimated that ∼2-5% of all pathogenic variants found in the four MMR genes in LS cases are detected in the gene. An overview of detected variants is presented here. Long-range (LR) polymerase chain reaction (PCR) and multiplex ligation probe amplification (MLPA) assays were used to detect variants in ∼1500 probands. In a subset of the probands, pathogenic variants were detected by next-generation sequencing, and all detected variants were confirmed by LR-PCR combined with an MLPA assay. A summary of mutation analyses performed on colon cancer patients from molecular diagnostic laboratories in Denmark and Sweden is presented. By screening ∼1500 HNPCC probands, a total of 40 different variants were detected in 71 probands (5%); 20 variants were classified as pathogenic (C5), 2 variants as likely pathogenic (C4), 15 variants as variants of unknown significance (VUSs) (C3), 1 variant as likely benign (C2), and 2 variants as benign (C1). In total, 22/71 (31%) of the probands carried a pathogenic sequence variant. Among the probands with isolated loss of pPMS2 expression, the fraction of pathogenic variants was 20/35 (55%). Approximately 5% of the probands found in the Danish and Swedish populations presented here carried a variant. In this study, six novel pathogenic variants and seven VUSs are reported.