{"doi":"10.1093/nar/gkr407","title":"Predicting the functional impact of protein mutations: application to cancer genomics","abstract":"As large-scale re-sequencing of genomes reveals many protein mutations, especially in human cancer tissues, prediction of their likely functional impact becomes important practical goal. Here, we introduce a new functional impact score (FIS) for amino acid residue changes using evolutionary conservation patterns. The information in these patterns is derived from aligned families and sub-families of sequence homologs within and between species using combinatorial entropy formalism. The score performs well on a large set of human protein mutations in separating disease-associated variants (∼19 200), assumed to be strongly functional, from common polymorphisms (∼35 600), assumed to be weakly functional (area under the receiver operating characteristic curve of ∼0.86). In cancer, using recurrence, multiplicity and annotation for ∼10 000 mutations in the COSMIC database, the method does well in assigning higher scores to more likely functional mutations ('drivers'). To guide experimental prioritization, we report a list of about 1000 top human cancer genes frequently mutated in one or more cancer types ranked by likely functional impact; and, an additional 1000 candidate cancer genes with rare but likely functional mutations. In addition, we estimate that at least 5% of cancer-relevant mutations involve switch of function, rather than simply loss or gain of function.","journal":"Nucleic Acids Research","year":2011,"id":2966,"datarank":16.748286700833138,"base_score":7.656810091480378,"endowment":7.656810091480378,"self_citation_contribution":1.1485215137220568,"citation_network_contribution":15.599765187111082,"self_endowment_contribution":1.1485215137220568,"citer_contribution":15.599765187111082,"corpus_percentile":86.4,"corpus_rank":2560,"citation_count":2114,"citer_count":188,"citers_with_citation_signal":188,"citers_with_endowment":188,"datacite_reuse_total":0,"is_dataset":false,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2011-07-03","authors":[{"id":1899,"name":"Yevgeniy Antipin","orcid":null,"position":1,"is_corresponding":false},{"id":14004,"name":"Jaswinder S. Samra","orcid":"0000-0001-6664-7147","position":2,"is_corresponding":false},{"id":1898,"name":"Boris Reva","orcid":"0000-0002-8805-389X","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}