Structural bioinformatics enhances mechanistic interpretation of genomic variation, demonstrated through the analyses of 935 distinct RAS family mutations

Abstract Motivation Protein-coding genetic alterations are frequently observed in Clinical Genetics, but the high yield of variants of uncertain significance remains a limitation in decision making. RAS-family GTPases are cancer drivers, but only 54 variants, across all family members, fall within w...

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Bibliographic Details
Published in:Bioinformatics Vol. 37; no. 10; pp. 1367 - 1375
Main Authors: Tripathi, Swarnendu, Dsouza, Nikita R, Urrutia, Raul, Zimmermann, Michael T
Format: Journal Article
Language:English
Published: England Oxford University Press 16.06.2021
Subjects:
Adult
Computational Biology
Genomics
Humans
Mutation, Missense
Neoplasms - genetics
Original Papers
ras Proteins - genetics
ISSN:1367-4803, 1367-4811, 1460-2059, 1367-4811
Online Access:Get full text
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Summary:Abstract Motivation Protein-coding genetic alterations are frequently observed in Clinical Genetics, but the high yield of variants of uncertain significance remains a limitation in decision making. RAS-family GTPases are cancer drivers, but only 54 variants, across all family members, fall within well-known hotspots. However, extensive sequencing has identified 881 non-hotspot variants for which significance remains to be investigated. Results Here, we evaluate 935 missense variants from seven RAS genes, observed in cancer, RASopathies and the healthy adult population. We characterized hotspot variants, previously studied experimentally, using 63 sequence- and 3D structure-based scores, chosen by their breadth of biophysical properties. Applying scores that display best correlation with experimental measures, we report new valuable mechanistic inferences for both hot-spot and non-hotspot variants. Moreover, we demonstrate that 3D scores have little-to-no correlation with those based on DNA sequence, which are commonly used in Clinical Genetics. Thus, combined, these new knowledge bear significant relevance. Availability and implementation All genomic and 3D scores, and markdown for generating figures, are provided in our supplemental data. Supplementary information Supplementary data are available at Bioinformatics online.
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ISSN:1367-4803
1367-4811
1460-2059
1367-4811
DOI:10.1093/bioinformatics/btaa972