Classification of VUS and Unclassified Variants in BRCT Repeats by Molecular Dynamics Simulation

Overview

Journal Comput Struct Biotechnol J

Specialty Biotechnology

Date 2020 Apr 8

PMID 32257056

Citations 34

Authors

Siddharth Sinha

San Ming Wang

Affiliations

Soon will be listed here.

Abstract

Pathogenic mutation in gene is one of the most penetrant genetic predispositions towards cancer. Identification of the mutation provides important aspect in prevention and treatment of the mutation-caused cancer. Of the large quantity of genetic variants identified in human , substantial portion is classified as Variant of Uncertain Significance (VUS) or unclassified variants due to the lack of functional evidence. In this study, we focused on the VUS and unclassified variants in BRCT repeat located at C-terminal. Utilizing the well-determined structure of BRCT repeats, we measured the influence of the variants on the structural conformations of BRCT repeats by using molecular dynamics simulation (MDS) consisting of RMSD (Root-mean-square-deviation), RMSF (Root-mean-square-fluctuations), Rg (Radius of gyration), SASA (Solvent accessible surface area), NH bond (hydrogen bond) and Covariance analysis. Using this approach, we analyzed 131 variants consisting of 89 VUS (Variant of Uncertain Significance) and 42 unclassified variants (unclassifiable by current methods) within BRCT repeats and were able to differentiate them into 78 Deleterious and 53 Tolerated variants. Comparing the results made by the saturation genome editing assay, multiple experimental assays, and reference databases shows that our approach provides high specificity, sensitivity and robust. Our study opens an avenue to classify VUS and unclassified variants in many cancer predisposition genes with known protein structure.

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