In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing

Abstract Over the years since the genetic testing of BRCA1 and BRCA2 has been conducted for research and later introduced into clinical practice, a high number of missense variants have been reported in the literature and deposited in public databases. Polymorphism Phenotyping v2 (PolyPhen-2) and So...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autor principal:	Kok-Siong Poon
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/21557b51d4c44773909f27a629f1c6b9
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:21557b51d4c44773909f27a629f1c6b9
record_format	dspace
spelling	oai:doaj.org-article:21557b51d4c44773909f27a629f1c6b92021-12-02T16:53:11ZIn silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing10.1038/s41598-021-88586-w2045-2322https://doaj.org/article/21557b51d4c44773909f27a629f1c6b92021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88586-whttps://doaj.org/toc/2045-2322Abstract Over the years since the genetic testing of BRCA1 and BRCA2 has been conducted for research and later introduced into clinical practice, a high number of missense variants have been reported in the literature and deposited in public databases. Polymorphism Phenotyping v2 (PolyPhen-2) and Sorting Intolerant from Tolerant (SIFT) are two widely applied bioinformatics tools used to assess the functional impacts of missense variants. A total of 2605 BRCA1 and 4763 BRCA2 variants from the ClinVar database were analysed with PolyPhen2 and SIFT. When SIFT was evaluated alongside PolyPhen-2 HumDiv and HumVar, it had shown top performance in terms of negative predictive value (NPV) (100%) and sensitivity (100%) for ClinVar classified benign and pathogenic BRCA1 variants. Both SIFT and PolyPhen-2 HumDiv achieved 100% NPV and 100% sensitivity in prediction of pathogenicity of the BRCA2 variants. Agreement was achieved in prediction outcomes from the three tested approaches in 55.04% and 68.97% of the variants of unknown significance (VUS) for BRCA1 and BRCA2, respectively. The performances of PolyPhen-2 and SIFT in predicting functional impacts varied across the two genes. Due to lack of high concordance in prediction outcomes among the two tested algorithms, their usefulness in classifying the pathogenicity of VUS identified through molecular testing of BRCA1 and BRCA2 is hence limited in the clinical setting.Kok-Siong PoonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kok-Siong Poon In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing
description	Abstract Over the years since the genetic testing of BRCA1 and BRCA2 has been conducted for research and later introduced into clinical practice, a high number of missense variants have been reported in the literature and deposited in public databases. Polymorphism Phenotyping v2 (PolyPhen-2) and Sorting Intolerant from Tolerant (SIFT) are two widely applied bioinformatics tools used to assess the functional impacts of missense variants. A total of 2605 BRCA1 and 4763 BRCA2 variants from the ClinVar database were analysed with PolyPhen2 and SIFT. When SIFT was evaluated alongside PolyPhen-2 HumDiv and HumVar, it had shown top performance in terms of negative predictive value (NPV) (100%) and sensitivity (100%) for ClinVar classified benign and pathogenic BRCA1 variants. Both SIFT and PolyPhen-2 HumDiv achieved 100% NPV and 100% sensitivity in prediction of pathogenicity of the BRCA2 variants. Agreement was achieved in prediction outcomes from the three tested approaches in 55.04% and 68.97% of the variants of unknown significance (VUS) for BRCA1 and BRCA2, respectively. The performances of PolyPhen-2 and SIFT in predicting functional impacts varied across the two genes. Due to lack of high concordance in prediction outcomes among the two tested algorithms, their usefulness in classifying the pathogenicity of VUS identified through molecular testing of BRCA1 and BRCA2 is hence limited in the clinical setting.
format	article
author	Kok-Siong Poon
author_facet	Kok-Siong Poon
author_sort	Kok-Siong Poon
title	In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing
title_short	In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing
title_full	In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing
title_fullStr	In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing
title_full_unstemmed	In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing
title_sort	in silico analysis of brca1 and brca2 missense variants and the relevance in molecular genetic testing
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/21557b51d4c44773909f27a629f1c6b9
work_keys_str_mv	AT koksiongpoon insilicoanalysisofbrca1andbrca2missensevariantsandtherelevanceinmoleculargenetictesting
_version_	1718382845526802432

In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing

Ejemplares similares