Advanced

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

Niroula, Abhishek LU and Vihinen, Mauno LU (2015) In Human Mutation 36(12). p.1128-1134
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... (More)
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/. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Mutation
volume
36
issue
12
pages
1128 - 1134
publisher
John Wiley & Sons
external identifiers
  • wos:000364788500002
  • pmid:26333163
  • scopus:84947023989
ISSN
1059-7794
DOI
10.1002/humu.22900
language
English
LU publication?
yes
id
a1f2a9fd-8758-4737-adb2-a2d7f484a16f (old id 8043398)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26333163?dopt=Abstract
date added to LUP
2015-10-04 19:14:46
date last changed
2017-10-22 03:18:46
@article{a1f2a9fd-8758-4737-adb2-a2d7f484a16f,
  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 reliable tool to prioritize variants for functional analysis. It is freely available at http://structure.bmc.lu.se/PON-MMR2/.},
  author       = {Niroula, Abhishek and Vihinen, Mauno},
  issn         = {1059-7794},
  language     = {eng},
  number       = {12},
  pages        = {1128--1134},
  publisher    = {John Wiley & Sons},
  series       = {Human Mutation},
  title        = {Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2.},
  url          = {http://dx.doi.org/10.1002/humu.22900},
  volume       = {36},
  year         = {2015},
}