Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2.
Variations in mismatch repair (MMR) system genes are causative of Lynch syndrome and other cancers. Thousands of variants have been identified in MMR genes, but the clinical relevance is known for only a small proportion. Recently, the InSiGHT group classified 2,360 MMR variants into five classes. One-third of variants, majority of which is nonsynonymous variants, remain to be of uncertain clinical relevance. Computational tools can be used to prioritize variants for disease relevance investigations. Previously, we classified 248 MMR variants as likely pathogenic and likely benign using PON-MMR. We have developed a novel tool, PON-MMR2, which is trained on a larger and more reliable dataset. In performance comparison, PON-MMR2 outperforms both generic tolerance prediction methods as well as methods optimized for MMR variants. It achieves accuracy and MCC of 0.89 and 0.78, respectively, in cross-validation and 0.86 and 0.69, respectively, on an independent test dataset. We classified 354 class 3 variants in InSiGHT database as well as all possible amino acid substitutions in four MMR proteins. Likely harmful variants mainly appear in the protein core, whereas likely benign variants are on the surface. PON-MMR2 is a highly reliable tool to prioritize variants for functional analysis. It is freely available at http://structure.bmc.lu.se/PON-MMR2/.
Department of Experimental Medical Science, Lund University, BMC B13, Lund, SE, 22184, Sweden.
Abhishek
A
Niroula
Department of Experimental Medical Science, Lund University, BMC B13, Lund, SE, 22184, Sweden.
Mauno
M
Vihinen
D019943:Amino Acid Substitution; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000737:chemistry / Q000235:genetics*; D030541:Databases, Genetic; D006801:Humans; D000069550:Machine Learning; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D015203:Reproducibility of Results; D012984:Software; D064878:Web Browser
D009687:Nuclear Proteins; D045643:DNA Repair Enzymes
Lynch syndrome; MMR; amino acid substitutions; computational tool; mismatch repair; missense mutation; prediction