ArticleGenome medicine2024
Using multiplexed functional data to reduce variant classification inequities in underrepresented populations.
Article in Genome medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Rare diseases in Brazil: a nationwide analysis of the diagnostic odyssey.Journal of community genetics · 2026Article
- 'Truthsets' for clinical validation of large-scale functional assays: Practice recommendations from Cancer Variant Interpretation Group UK (CanVIG-UK).medRxiv : the preprint server for health sciences · 2026Article
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- An integrated cardiometabolic genetic testing program in a predominantly Hispanic population within a community setting.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Not Forgotten: Patient Experiences with Genetic Variant Reclassifications.medRxiv : the preprint server for health sciences · 2026Article
- Germline Genetic Testing in Breast and Gynecologic Cancers: Evaluating Age at Diagnosis as a Determinant.Cancers · 2026Article
- Massively parallel functional genomic assays in endocrinology: from promise to delivery.Journal of molecular endocrinology · 2026Review
- Genetic analysis of neurodegenerative diseases.The Journal of clinical investigation · 2026Review
- Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.Nature reviews. Cardiology · 2026Review
- A scalable approach to resolving variants of uncertain significance.bioRxiv : the preprint server for biology · 2026Article
- The functional landscape of coding variation in the familial hypercholesterolemia geneScience (New York, N.Y.) · 2026Article
- Ancestry-specific performance of variant effect predictors in clinical variant classification.bioRxiv : the preprint server for biology · 2026Article
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- MaveMD: A functional data resource for genomic medicine.medRxiv : the preprint server for health sciences · 2025Article
- GREGoR: accelerating genomics for rare diseases.Nature · 2025Article
- Saturation mapping of MUTYH variant effects using DNA repair reporters.American journal of human genetics · 2025Article
- Validating data from multiplex assays of variant effect: A CanVIG-UK national survey of NHS clinical scientists.American journal of human genetics · 2025Article
- Insights on improving accessibility and usability of functional data to unlock their potential for variant interpretation.American journal of human genetics · 2025Article
- Review
- Beyond single references: pangenome graphs and the future of genomic medicine.Frontiers in genetics · 2025Review
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18 authors.
Funding
Abstract
backgroundMultiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style functional data may help resolve variant classification disparities between populations, especially for Variants of Uncertain Significance (VUS).
methodsWe analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry from All of Us and the Genome Aggregation Database. Then, we incorporated clinically calibrated MAVE data into the Clinical Genome Resource's Variant Curation Expert Panel rules to automate VUS reclassification for BRCA1, TP53, and PTEN.
resultsUsing two orthogonal statistical approaches, we show a higher prevalence (p ≤ 5.95e - 06) of VUS in individuals of non-European-like genetic ancestry across all medical specialties assessed in all three databases. Further, in the non-European-like genetic ancestry group, higher rates of Benign or Likely Benign and variants with no clinical designation (p ≤ 2.5e - 05) were found across many medical specialties, whereas Pathogenic or Likely Pathogenic assignments were increased in individuals of European-like genetic ancestry (p ≤ 2.5e - 05). Using MAVE data, we reclassified VUS in individuals of non-European-like genetic ancestry at a significantly higher rate in comparison to reclassified VUS from European-like genetic ancestry (p = 9.1e - 03) effectively compensating for the VUS disparity. Further, essential code analysis showed equitable impact of MAVE evidence codes but inequitable impact of allele frequency (p = 7.47e - 06) and computational predictor (p = 6.92e - 05) evidence codes for individuals of non-European-like genetic ancestry.
conclusionsGeneration of saturation-style MAVE data should be a priority to reduce VUS disparities and produce equitable training data for future computational predictors.
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