BRCA1- and BRCA2-specific in silico tools for variant interpretation in the CAGI 5 ENIGMA challenge.
bioinformatics
breast cancer
functional assays
gene-specific predictor
homology-directed DNA repair (HDR)
molecular diagnosis
ovarian cancer
pathogenicity predictions
protein-specific predictor
splicing predictions
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
08
01
2019
revised:
15
05
2019
accepted:
17
05
2019
pubmed:
22
5
2019
medline:
14
3
2020
entrez:
22
5
2019
Statut:
ppublish
Résumé
BRCA1 and BRCA2 (BRCA1/2) germline variants disrupting the DNA protective role of these genes increase the risk of hereditary breast and ovarian cancers. Correct identification of these variants then becomes clinically relevant, because it may increase the survival rates of the carriers. Unfortunately, we are still unable to systematically predict the impact of BRCA1/2 variants. In this article, we present a family of in silico predictors that address this problem, using a gene-specific approach. For each protein, we have developed two tools, aimed at predicting the impact of a variant at two different levels: Functional and clinical. Testing their performance in different datasets shows that specific information compensates the small number of predictive features and the reduced training sets employed to develop our models. When applied to the variants of the BRCA1/2 (ENIGMA) challenge in the fifth Critical Assessment of Genome Interpretation (CAGI 5) we find that these methods, particularly those predicting the functional impact of variants, have a good performance, identifying the large compositional bias towards neutral variants in the CAGI sample. This performance is further improved when incorporating to our prediction protocol estimates of the impact on splicing of the target variant.
Identifiants
pubmed: 31112341
doi: 10.1002/humu.23802
pmc: PMC6744361
mid: NIHMS1031229
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1593-1611Subventions
Organisme : Fundación Científica Asociación Española Contra el Cáncer
Pays : International
Organisme : Ministerio de Economía y Competitividad
ID : SAF2016-80255-R
Pays : International
Organisme : European Regional Development Fund
ID : Pirepred (EFA086/15)
Pays : International
Organisme : Instituto de Salud Carlos III
ID : PI13/01711
Pays : International
Organisme : Foundation for the National Institutes of Health
ID : NIH R13 HG006650
Pays : International
Organisme : NHGRI NIH HHS
ID : R13 HG006650
Pays : United States
Organisme : Instituto de Salud Carlos III
ID : PI15/00355
Pays : International
Organisme : NHGRI NIH HHS
ID : U41 HG007346
Pays : United States
Organisme : Instituto de Salud Carlos III
ID : Miguel Servet Progam [CP16/00034]
Pays : International
Organisme : Instituto de Salud Carlos III
ID : PI12/02585
Pays : International
Organisme : Instituto de Salud Carlos III
ID : PI16/01218
Pays : International
Organisme : Foundation for the National Institutes of Health
ID : NIH U41 HG007346
Pays : International
Organisme : European Regional Development Fund
ID : Interreg program POCTEFA
Pays : International
Organisme : Ministerio de Economía y Competitividad
ID : BIO2012-40133
Pays : International
Informations de copyright
© 2019 Wiley Periodicals, Inc.
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