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Comprehensive Identification of Deleterious TP53 Missense VUS Variants Based on Their Impact on TP53 Structural Stability

Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China
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Academic Editors: Paola Ghiorzo and Apostolos Zaravinos
Int. J. Mol. Sci. 2021, 22(21), 11345; https://doi.org/10.3390/ijms222111345
Received: 26 August 2021 / Revised: 13 October 2021 / Accepted: 14 October 2021 / Published: 20 October 2021
(This article belongs to the Section Molecular Genetics and Genomics)
TP53 plays critical roles in maintaining genome stability. Deleterious genetic variants damage the function of TP53, causing genome instability and increased cancer risk. Of the large quantity of genetic variants identified in TP53, however, many remain functionally unclassified as variants of unknown significance (VUS) due to the lack of evidence. This is reflected by the presence of 749 (42%) VUS of the 1785 germline variants collected in the ClinVar database. In this study, we addressed the deleteriousness of TP53 missense VUS. Utilizing the protein structure-based Ramachandran Plot-Molecular Dynamics Simulation (RPMDS) method that we developed, we measured the effects of missense VUS on TP53 structural stability. Of the 340 missense VUS tested, we observed deleterious evidence for 193 VUS, as reflected by the TP53 structural changes caused by the VUS-substituted residues. We compared the results from RPMDS with those from other in silico methods and observed higher specificity of RPMDS in classification of TP53 missense VUS than these methods. Data from our current study address a long-standing challenge in classifying the missense VUS in TP53, one of the most important tumor suppressor genes. View Full-Text
Keywords: TP53; VUS; deleterious; molecular dynamic simulations; ramachandran plot TP53; VUS; deleterious; molecular dynamic simulations; ramachandran plot
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MDPI and ACS Style

Tam, B.; Sinha, S.; Qin, Z.; Wang, S.M. Comprehensive Identification of Deleterious TP53 Missense VUS Variants Based on Their Impact on TP53 Structural Stability. Int. J. Mol. Sci. 2021, 22, 11345. https://doi.org/10.3390/ijms222111345

AMA Style

Tam B, Sinha S, Qin Z, Wang SM. Comprehensive Identification of Deleterious TP53 Missense VUS Variants Based on Their Impact on TP53 Structural Stability. International Journal of Molecular Sciences. 2021; 22(21):11345. https://doi.org/10.3390/ijms222111345

Chicago/Turabian Style

Tam, Benjamin, Siddharth Sinha, Zixin Qin, and San M. Wang. 2021. "Comprehensive Identification of Deleterious TP53 Missense VUS Variants Based on Their Impact on TP53 Structural Stability" International Journal of Molecular Sciences 22, no. 21: 11345. https://doi.org/10.3390/ijms222111345

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