Functional Assessment of Genetic Variants with Outcomes Adapted to Clinical Decision-Making.

Abstract:

: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.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Thouvenot P,Ben Yamin B,Fourrière L,Lescure A,Boudier T,Del Nery E,Chauchereau A,Goldgar DE,Houdayer C,Stoppa-Lyonnet D,Nicolas A,Millot GA

doi

10.1371/journal.pgen.1006096

subject

Has Abstract

pub_date

2016-06-06 00:00:00

pages

e1006096

issue

6

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-16-00586

journal_volume

12

pub_type

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