ArticlePLoS genetics2016
Functional Assessment of Genetic Variants with Outcomes Adapted to Clinical Decision-Making.
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Functional Characterization of the Human BRCA1 ∆11 Splicing Isoforms in Yeast.International journal of molecular sciences · 2024Article
- Article
- Resources and tools for rare disease variant interpretation.Frontiers in molecular biosciences · 2023Review
- Refinement of the assignment to the ACMG/AMP BS3 and PS3 criteria of eightFrontiers in oncology · 2023Article
- Validation and Data-Integration of Yeast-Based Assays for Functional Classification of BRCA1 Missense Variants.International journal of molecular sciences · 2022Article
- Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach.American journal of human genetics · 2021Article
- Technological Improvements in the Genetic Diagnosis of Rett Syndrome Spectrum Disorders.International journal of molecular sciences · 2021Review
- Article
- Yeast as a Tool to Understand the Significance of Human Disease-Associated Gene Variants.Genes · 2021Review
- ExploringMicrobial cell (Graz, Austria) · 2021Review
- Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation.Journal of medical genetics · 2020Review
- Yeast-based assays for the functional characterization of cancer-associated variants of human DNA repair genes.Microbial cell (Graz, Austria) · 2020Review
- Functional analysis of clinicalCold Spring Harbor molecular case studies · 2019Article
- Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation.The Journal of biological chemistry · 2019Article
- Article
- Functional Interaction BetweenFrontiers in genetics · 2018Article
Corrections and comments
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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