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This article is part of the supplement: SNP-SIG 2012: Identification and annotation of SNPs in the context of structure, function, and disease

Open Access Open Badges Research

Assessment of computational methods for predicting the effects of missense mutations in human cancers

Florian Gnad, Albion Baucom, Kiran Mukhyala, Gerard Manning and Zemin Zhang*

Author Affiliations

Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA 94080, USA

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BMC Genomics 2013, 14(Suppl 3):S7  doi:10.1186/1471-2164-14-S3-S7

Published: 28 May 2013



Recent advances in sequencing technologies have greatly increased the identification of mutations in cancer genomes. However, it remains a significant challenge to identify cancer-driving mutations, since most observed missense changes are neutral passenger mutations. Various computational methods have been developed to predict the effects of amino acid substitutions on protein function and classify mutations as deleterious or benign. These include approaches that rely on evolutionary conservation, structural constraints, or physicochemical attributes of amino acid substitutions. Here we review existing methods and further examine eight tools: SIFT, PolyPhen2, Condel, CHASM, mCluster, logRE, SNAP, and MutationAssessor, with respect to their coverage, accuracy, availability and dependence on other tools.


Single nucleotide polymorphisms with high minor allele frequencies were used as a negative (neutral) set for testing, and recurrent mutations from the COSMIC database as well as novel recurrent somatic mutations identified in very recent cancer studies were used as positive (non-neutral) sets. Conservation-based methods generally had moderately high accuracy in distinguishing neutral from deleterious mutations, whereas the performance of machine learning based predictors with comprehensive feature spaces varied between assessments using different positive sets. MutationAssessor consistently provided the highest accuracies. For certain combinations metapredictors slightly improved the performance of included individual methods, but did not outperform MutationAssessor as stand-alone tool.


Our independent assessment of existing tools reveals various performance disparities. Cancer-trained methods did not improve upon more general predictors. No method or combination of methods exceeds 81% accuracy, indicating there is still significant room for improvement for driver mutation prediction, and perhaps more sophisticated feature integration is needed to develop a more robust tool.