Comprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability

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 unkno...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Benjamin Tam, Siddharth Sinha, Zixin Qin, San Ming Wang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	TP53 VUS deleterious molecular dynamic simulations ramachandran plot Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/d686216fec31441fbecea20b6d37fecd
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:d686216fec31441fbecea20b6d37fecd
record_format	dspace
spelling	oai:doaj.org-article:d686216fec31441fbecea20b6d37fecd2021-11-11T16:49:26ZComprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability10.3390/ijms2221113451422-00671661-6596https://doaj.org/article/d686216fec31441fbecea20b6d37fecd2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11345https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067TP53 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.Benjamin TamSiddharth SinhaZixin QinSan Ming WangMDPI AGarticleTP53VUSdeleteriousmolecular dynamic simulationsramachandran plotBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11345, p 11345 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TP53 VUS deleterious molecular dynamic simulations ramachandran plot Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	TP53 VUS deleterious molecular dynamic simulations ramachandran plot Biology (General) QH301-705.5 Chemistry QD1-999 Benjamin Tam Siddharth Sinha Zixin Qin San Ming Wang Comprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability
description	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.
format	article
author	Benjamin Tam Siddharth Sinha Zixin Qin San Ming Wang
author_facet	Benjamin Tam Siddharth Sinha Zixin Qin San Ming Wang
author_sort	Benjamin Tam
title	Comprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability
title_short	Comprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability
title_full	Comprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability
title_fullStr	Comprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability
title_full_unstemmed	Comprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability
title_sort	comprehensive identification of deleterious <i>tp53</i> missense vus variants based on their impact on tp53 structural stability
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d686216fec31441fbecea20b6d37fecd
work_keys_str_mv	AT benjamintam comprehensiveidentificationofdeleteriousitp53imissensevusvariantsbasedontheirimpactontp53structuralstability AT siddharthsinha comprehensiveidentificationofdeleteriousitp53imissensevusvariantsbasedontheirimpactontp53structuralstability AT zixinqin comprehensiveidentificationofdeleteriousitp53imissensevusvariantsbasedontheirimpactontp53structuralstability AT sanmingwang comprehensiveidentificationofdeleteriousitp53imissensevusvariantsbasedontheirimpactontp53structuralstability
_version_	1718432268890931200

Comprehensive Identification of Deleterious <i>TP53</i> Missense VUS Variants Based on Their Impact on TP53 Structural Stability

Ejemplares similares