Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2

Human Mutation
Abhishek Niroula, Mauno Vihinen

Abstract

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 reliab...Continue Reading

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Citations

Feb 23, 2017·Human Mutation·Abhishek Niroula, Mauno Vihinen
Dec 1, 2017·BMC Bioinformatics·Jelena Čalyševa, Mauno Vihinen
Mar 19, 2016·Human Mutation·Abhishek Niroula, Mauno Vihinen
Mar 31, 2018·International Journal of Molecular Sciences·Yang YangMauno Vihinen
Dec 1, 2018·BMC Bioinformatics·Gerard C P Schaafsma, Mauno Vihinen
Feb 6, 2020·Database : the Journal of Biological Databases and Curation·Anasua SarkarMauno Vihinen
Sep 16, 2016·Human Mutation·Rossella TricaricoUNKNOWN InSiGHT Variant Interpretation Committee
Aug 8, 2021·International Journal of Molecular Sciences·Yang YangMauno Vihinen

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