ArticleGenome biology2022
Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome.
Article in Genome biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 39 citations in OpenAlex.
- Validation structures for sequence variants of uncertain significance in hereditary cancer.European journal of human genetics : EJHG · 2026Review
- A scalable approach to resolving variants of uncertain significance.bioRxiv : the preprint server for biology · 2026Article
- Lynch Syndrome as a Spectrum of Four Distinct Genetic Disorders: Toward Genotype-Guided Precision Management in the NGS Era.Cancers · 2026Review
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- A novel frameshift variant inFrontiers in medicine · 2026Article
- Landscapes of missense variant impact for human superoxide dismutase 1.American journal of human genetics · 2025Article
- Availability of benign missense variant "truthsets" for validation of functional assays: Current status and a systematic approach.American journal of human genetics · 2025Article
- RNA-based diagnostic studies in genetics: Review and guidance from a multidisciplinary French network.European journal of human genetics : EJHG · 2025Review
- Saturation mapping of MUTYH variant effects using DNA repair reporters.American journal of human genetics · 2025Article
- Comprehensively Testing the Function of Missense Variation in thebioRxiv : the preprint server for biology · 2025Article
- Insights on improving accessibility and usability of functional data to unlock their potential for variant interpretation.American journal of human genetics · 2025Article
- High-throughput screening of human genetic variants by pooled prime editing.Cell genomics · 2025Article
- Multiplex, multimodal mapping of variant effects in secreted proteins.bioRxiv : the preprint server for biology · 2025Article
- MaveDB 2024: a curated community database with over seven million variant effects from multiplexed functional assays.Genome biology · 2025Article
- A missense variant effect map for the human tumor-suppressor protein CHK2.American journal of human genetics · 2024Article
- Using multiplexed functional data to reduce variant classification inequities in underrepresented populations.Genome medicine · 2024Article
- Understanding genetic variants in context.eLife · 2024Article
- ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.Nature communications · 2024Article
- Leaving no patient behind! Expert recommendation in the use of innovative technologies for diagnosing rare diseases.Orphanet journal of rare diseases · 2024Review
- Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundLynch syndrome (LS) is a cancer predisposition syndrome affecting more than 1 in every 300 individuals worldwide. Clinical genetic testing for LS can be life-saving but is complicated by the heavy burden of variants of uncertain significance (VUS), especially missense changes.
resultTo address this challenge, we leverage a multiplexed analysis of variant effect (MAVE) map covering >94% of the 17,746 possible missense variants in the key LS gene MSH2. To establish this map's utility in large-scale variant reclassification, we overlay it on clinical databases of >15,000 individuals with LS gene variants uncovered during clinical genetic testing. We validate these functional measurements in a cohort of individuals with paired tumor-normal test results and find that MAVE-based function scores agree with the clinical interpretation for every one of the MSH2 missense variants with an available classification. We use these scores to attempt reclassification for 682 unique missense VUS, among which 34 scored as deleterious by our function map, in line with previously published rates for other cancer predisposition genes. Combining functional data and other evidence, ten missense VUS are reclassified as pathogenic/likely pathogenic, and another 497 could be moved to benign/likely benign. Finally, we apply these functional scores to paired tumor-normal genetic tests and identify a subset of patients with biallelic somatic loss of function, reflecting a sporadic Lynch-like Syndrome with distinct implications for treatment and relatives' risk.
conclusionThis study demonstrates how high-throughput functional assays can empower scalable VUS resolution and prospectively generate strong evidence for variant classification.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.