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The International Society for Gastrointestinal Hereditary Tumors (InSIGHT) has established a committee (Variant Interpretation Committee; VIC) for the interpretation of sequence variants in the mismatch repair (MMR) genes associated with Lynch syndrome (LS). One of the major steps involved in this process has been the establishment of qualitative specific classification rules for the MMR genes, with the aim to improve the clinical utility of MMR gene testing. The 5-class variant classification system proposed by the International Agency for Research on Cancer (IARC) was used to this purpose, since it links all classes to specific clinical recommendations. Multiple lines of evidence were required for class assignment and in order to classify a variant as pathogenic or likely pathogenic, (Classes 5 and 4, respectively), or as not pathogenic or likely not pathogenic (Classes 1 and 2, respectively), concordant evidence derived from both clinical and functional datasets had to be available. Variants with discordant information or with lack of either clinical or functional information, were considered of uncertain significance (Class 3). The following specific points of evidence were considered: 1. Type of sequence variation; 2) functional protein assays; 3) mRNA assays; 4) phenotype associated in compound heterozygotes for the variant under scrutiny and a clearly pathogenic variant in the same gene; 5) presence of the variant on different haplotypes across LS families; 6) co-segregation data and clinical phenotype; 7) tumor molecular characteristics; 8) population frequency; 9) risk estimated from case-control studies. Since interpretation of functional assays proved to be difficult and variable across committee members, specific supporting information and flowcharts were developed. In addition, whenever available, quantitative multifactorial analysis2 was used and the outcome compared to that of qualitative assessment. The classification scheme was modified by consensus to accommodate new data and inconsistencies over multiple classification teleconferences and face-to-face meetings. Overall, the rules were successfully applied to classify 2,360 variants lodged onto the InSiGHT database. These criteria provide a baseline for standardized clinical classification of MMR gene sequence variation that may be linked to patient and family management in the genetic counseling arena according to published guidelines.