Functional Assessment of Genetic Variants with Outcomes Adapted to Clinical Decision-Making.
Understanding the medical effect of an ever-growing number of human variants detected is a long term challenge in genetic counseling. Functional assays, based on in vitro or in vivo evaluations of the variant effects, provide essential information, but they require robust statistical validation, as well as adapted outputs, to be implemented in the clinical decision-making process. Here, we assessed 25 pathogenic and 15 neutral missense variants of the BRCA1 breast/ovarian cancer susceptibility gene in four BRCA1 functional assays. Next, we developed a novel approach that refines the variant ranking in these functional assays. Lastly, we developed a computational system that provides a probabilistic classification of variants, adapted to clinical interpretation. Using this system, the best functional assay exhibits a variant classification accuracy estimated at 93%. Additional theoretical simulations highlight the benefit of this ready-to-use system in the classification of variants after functional assessment, which should facilitate the consideration of functional evidences in the decision-making process after genetic testing. Finally, we demonstrate the versatility of the system with the classification of siRNAs tested for human cell growth inhibition in high throughput screening.
Institut Curie, PSL Research University, Paris, France.|CNRS UMR 3244, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
Pierre
P
Thouvenot
Institut Curie, PSL Research University, Paris, France.|CNRS UMR 3244, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
Barbara
B
Ben Yamin
Institut Curie, PSL Research University, Paris, France.|CNRS UMR 3244, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
Lou
L
Fourrière
Institut Curie, PSL Research University, Department of Translational Research, the Biophenics High-Content Screening Laboratory, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris, France.
Aurianne
A
Lescure
Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
Thomas
T
Boudier
Institut Curie, PSL Research University, Department of Translational Research, the Biophenics High-Content Screening Laboratory, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris, France.
Elaine
E
Del Nery
INSERM U981, Villejuif, France.|Univ Paris-Sud, UMR981, Villejuif, France.|Institut Gustave Roussy, Villejuif, France.
Anne
A
Chauchereau
Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
David E
DE
Goldgar
Service de Génétique Oncologique, Institut Curie, Paris, France.|INSERM U830, Paris, France.|Université Paris Descartes, Paris, France.
Claude
0000-0002-5190-0389
C
Houdayer
Service de Génétique Oncologique, Institut Curie, Paris, France.|INSERM U830, Paris, France.|Université Paris Descartes, Paris, France.
Dominique
D
Stoppa-Lyonnet
Institut Curie, PSL Research University, Paris, France.|CNRS UMR 3244, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
Alain
A
Nicolas
Institut Curie, PSL Research University, Paris, France.|CNRS UMR 3244, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
Gaël A
GA
Millot
D019313:BRCA1 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D000066491:Clinical Decision-Making; D005260:Female; D005817:Genetic Counseling / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D020125:Mutation, Missense / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human