Structural Bioinformatics Enhances Mechanistic Interpretation of Genomic Variation, Demonstrated Through the Analyses of 935 Distinct RAS Family Mutations

摘要: Motivation Protein-coding genetic alterations are frequently observed in Clinical Genetics, but the high yield of variants uncertain significance (VUS) remains a limitation decision making. RAS-family GTPases cancer drivers, only 54 variants, across all family members, fall within well-known hotspots. However, extensive sequencing has identified 881 non-hotspot for which to be investigated. Results Here, we evaluate 935 missense from seven RAS genes, cancer, RASopathies, and healthy adult population. We characterized hotspot previously studied experimentally, using 63 sequence- 3 D structure-based scores, chosen by their breadth biophysical properties. Applying scores that display best correlation with experimental measures, report new valuable mechanistic inferences both hot-spot variants. Moreover, demonstrate have little-to-no those based on DNA sequence, commonly used Genetics. Thus, combined, these knowledge bear significant relevance. Supplementary information data available at Bioinformatics online.