Accurate classification ofMLH1/MSH2missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR)

Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR).

Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), is the most common known genetic syndrome for colorectal cancer (CRC). MLH1/MSH2 mutations underlie approximately 90% of Lynch syndrome families. A total of 24% of these mutations are missense. Interpreting missense variation is extremely challenging. We have therefore developed multivariate analysis of protein polymorp...

Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.

Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that confer colon cancer su...

Epimutation in DNA Mismatch Repair (MMR) Genes

The InSiGHT approach to classification of mismatch repair gene variants

The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) is committed to the sharing of MMR variant information through the publicly accessible InSiGHT database. This amalgamation of various types of data related to MMR variants and Lynch Syndrome encompasses family history, tumour pathology, genotype, RNA, in silico and in vitro information sourced from published literature ...

Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors.

PURPOSE There is a paucity of data quantifying the familial risk of colorectal cancer associated with mismatch repair (MMR)-deficient and MMR-stable tumors. To address this, we analyzed a population-based series of 1,042 colorectal cancer probands with verified family histories. EXPERIMENTAL DESIGN Constitutional DNA from probands was systematically screened for MYH variants and those with ca...