ArticleCancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology2011
A computational method to classify variants of uncertain significance using functional assay data with application to BRCA1.
Article in Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed.
- Functional assays for BRCA1 and BRCA2 variant analysis: new tools and their applications.NPJ breast cancer · 2026Review
- Article
- Assessment ofJCO clinical cancer informatics · 2024Article
- Saturation genome editing of 11 codons and exon 13 of BRCA2 coupled with chemotherapeutic drug response accurately determines pathogenicity of variants.PLoS genetics · 2023Article
- Correspondence between functional scores from deep mutational scans and predicted effects on protein stability.Protein science : a publication of the Protein Society · 2023Article
- BRCT Domains: Structure, Functions, and Implications in Disease-New Therapeutic Targets for Innovative Drug Discovery against Infections.Pharmaceutics · 2023Review
- Assessment of small in-frame indels and C-terminal nonsense variants of BRCA1 using a validated functional assay.Scientific reports · 2022Article
- An integrative model for the comprehensive classification of BRCA1 and BRCA2 variants of uncertain clinical significance.NPJ genomic medicine · 2022Article
- Detection of Germline Variants in 450 Breast/Ovarian Cancer Families with a Multi-Gene Panel Including Coding and Regulatory Regions.International journal of molecular sciences · 2021Article
- A computational model for classification of BRCA2 variants using mouse embryonic stem cell-based functional assays.NPJ genomic medicine · 2020Article
- 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
- A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor.Nucleic acids research · 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
- Trans-activation-based risk assessment of BRCA1 BRCT variants with unknown clinical significance.Human genomics · 2018Article
- Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.American journal of human genetics · 2018Article
- ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants.Genome medicine · 2017Article
- Characterization of Promiscuous Binding of Phosphor Ligands to Breast-Cancer-Gene 1 (BRCA1) C-Terminal (BRCT): Molecular Dynamics, Free Energy, Entropy and Inhibitor Design.PLoS computational biology · 2016Article
- Functional Assessment of Genetic Variants with Outcomes Adapted to Clinical Decision-Making.PLoS genetics · 2016Article
- Genomic Biomarkers for Breast Cancer Risk.Advances in experimental medicine and biology · 2016Review
- Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance.NPJ genomic medicine · 2016Article
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5 authors.
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Abstract
backgroundBesides revealing cancer predisposition variants or the absence of any changes, genetic testing for cancer predisposition genes can also identify variants of uncertain clinical significance (VUS). Classifying VUSs is a pressing problem, as ever more patients seek genetic testing for disease syndromes and receive noninformative results from those tests. In cases such as the breast and ovarian cancer syndrome in which prophylactic options can be severe and life changing, having information on the disease relevance of the VUS that a patient harbors can be critical.
methodsWe describe a computational approach for inferring the disease relevance of VUSs in disease genes from data derived from an in vitro functional assay. It is based on a Bayesian hierarchical model that accounts for sources of experimental heterogeneity.
resultsThe functional data correlate well with the pathogenicity of BRCA1 BRCT VUSs, thus providing evidence regarding pathogenicity when family and genetic data are absent or uninformative.
conclusionsWe show the utility of the model by using it to classify 76 VUSs located in the BRCT region of BRCA1. The approach is both sensitive and specific when evaluated on variants previously classified using independent sources of data. Although the functional data are very informative, they will need to be combined with other forms of data to meet the more stringent requirements of clinical application. IMPACT: Our work will lead to improved classification of VUSs and will aid in the clinical decision making of their carriers.
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