title: Predicting phenotypic severity of uncertain gene variants in the RET proto-oncogene.
abstract: Although reported gene variants in the RET oncogene have been directly associated with multiple endocrine neoplasia type 2 and hereditary medullary thyroid carcinoma, other mutations are classified as variants of uncertain significance (VUS) until the associated clinical phenotype is made clear. Currently, some 46 non-synonymous VUS entries exist in curated archives. In the absence of a gold standard method for predicting phenotype outcomes, this follow up study applies feature selected amino acid physical and chemical properties feeding a Bayes classifier to predict disease association of uncertain gene variants into categories of benign and pathogenic. Algorithm performance and VUS predictions were compared to established phylogenetic based mutation prediction algorithms. Curated outcomes and unpublished RET gene variants with known disease association were used to benchmark predictor performance. Reliable classification of RET uncertain gene variants will augment current clinical information of RET mutations and assist in improving prediction algorithms as knowledge increases.
authors.affiliation: Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, Utah, United States of America. david.crockett@aruplab.com
authors.forename: David K
authors.initials: DK
authors.lastname: Crockett
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Piccolo
authors.forename: Perry G
authors.initials: PG
authors.lastname: Ridge
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Margraf
authors.forename: Elaine
authors.initials: E
authors.lastname: Lyon
authors.forename: Marc S
authors.initials: MS
authors.lastname: Williams
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000465:Algorithms; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000737:chemistry / Q000235:genetics*; D035501:Uncertainty
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret