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Article

Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants

1
Research Unit in Clinical and Translational Bioinformatics, Vall d’Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
2
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Valentina Silvestri
Int. J. Mol. Sci. 2021, 22(12), 6226; https://doi.org/10.3390/ijms22126226
Received: 24 April 2021 / Revised: 27 May 2021 / Accepted: 4 June 2021 / Published: 9 June 2021
(This article belongs to the Special Issue Advances in the Molecular Basis of BRCA-Associated Cancers)
The present limitations in the pathogenicity prediction of BRCA1 and BRCA2 (BRCA1/2) missense variants constitute an important problem with negative consequences for the diagnosis of hereditary breast and ovarian cancer. However, it has been proposed that the use of endophenotype predictions, i.e., computational estimates of the outcomes of functional assays, can be a good option to address this bottleneck. The application of this idea to the BRCA1/2 variants in the CAGI 5-ENIGMA international challenge has shown promising results. Here, we developed this approach, exploring the predictive performances of the regression models applied to the BRCA1/2 variants for which the values of the homology-directed DNA repair and saturation genome editing assays are available. Our results first showed that we can generate endophenotype estimates using a few molecular-level properties. Second, we show that the accuracy of these estimates is enough to obtain pathogenicity predictions comparable to those of many standard tools. Third, endophenotype-based predictions are complementary to, but do not outperform, those of a Random Forest model trained using variant pathogenicity annotations instead of endophenotype values. In summary, our results confirmed the usefulness of the endophenotype approach for the pathogenicity prediction of the BRCA1/2 missense variants, suggesting different options for future improvements. View Full-Text
Keywords: BRCA1; BRCA2; endophenotype; breast cancer; functional assays; pathogenicity predictions; homology-directed DNA repair (HDR); molecular diagnosis; ovarian cancer; protein-specific predictor BRCA1; BRCA2; endophenotype; breast cancer; functional assays; pathogenicity predictions; homology-directed DNA repair (HDR); molecular diagnosis; ovarian cancer; protein-specific predictor
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MDPI and ACS Style

Özkan, S.; Padilla, N.; de la Cruz, X. Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants. Int. J. Mol. Sci. 2021, 22, 6226. https://doi.org/10.3390/ijms22126226

AMA Style

Özkan S, Padilla N, de la Cruz X. Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants. International Journal of Molecular Sciences. 2021; 22(12):6226. https://doi.org/10.3390/ijms22126226

Chicago/Turabian Style

Özkan, Selen, Natàlia Padilla, and Xavier de la Cruz. 2021. "Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants" International Journal of Molecular Sciences 22, no. 12: 6226. https://doi.org/10.3390/ijms22126226

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