Workshop report: the clinical application of data from multiplex assays of variant effect (MAVEs), 12 July 2023
Open accessAbstract
Clinical classification of genomic variants identified on sequencing is often challenging, with many variants classified as Variants of Uncertain Significance (VUS) on account of insufficient evidence. Advances in sequencing and gene synthesis has made feasible multiplexed assays of variant effect (MAVEs), which quantify the functional impact of many thousands of genomic variants in a single experiment. These assays and the functional evidence they generate have the potential to empower more accurate clinical variant classification. However, there are many outstanding challenges and opportunities that require joint resolution and specification, thus necessitating communication between the research scientists who have designed and performed MAVEs and the clinicians and diagnostic scientists who will apply their data to clinical variant classification. In the ‘Clinical Application of MAVE Data’ workshop, held on 12th July 2023 at the Wellcome Connecting Science Conference Centre in between two relevant research meetings, ‘Curating the Clinical Genome 2023’ and the ‘Mutational Scanning Symposium 2023’, 44 key scientific and/or clinical stakeholders were brought together to consider important questions relating to clinical application of MAVE data, such as quantitative validation, variant truth-sets, platforms and standards for dissemination of MAVE data. The outcomes and possible next steps that were discussed encompassed development of focused workshops to develop consensus recommendations, creating a MAVE evaluation working group, and collaboration of ClinVar and MaveDB to enact software changes that support enhanced functional data submission.
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Rigorous functional studies are considered strong evidence (PS3/BS3) by the widely used American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) genetic diagnostic guidelines.
“Rigorous functional studies are considered strong evidence (PS3/BS3) by the widely used American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) genetic diagnostic guidelines.”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [39]
The Introduction says the ACMG/AMP framework weights variant-classification criteria by evidence strength and describes clinical validation of functional assays. The References identify PS3/BS3 as the functional-evidence criterion. However, the report does not state that rigorous functional studies are assigned strong evidence under both PS3 and BS3; it says assay evidence strength is assessed and quantified through validation. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn the context of a Bayesian decision-making framework, rigorous functional studies can effectively play a deterministic role in classifying variants.
“In the context of a Bayesian decision-making framework they can effectively play a deterministic role in classifying variants (25, 38, 39), thereby potentially making major inroads into the ‘VUS problem’.”
From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [39]
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Cites
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Cited by
Sorted by citations
Massively parallel functional genomic assays in endocrinology: from promise to delivery
Xu, J., Aslanzadeh, V., Kudla, G., & Semple, R. K. (2026) · Journal of Molecular Endocrinology · doi:10.1530/jme-25-0134
- Authors
- Allen, S., Garrett, A., Muffley, L., Fayer, S., Foreman, J., Adams, D. J., Hurles, M., Rubin, A. F., Roth, F. P., Starita, L. M., Biesecker, L. G., & Turnbull, C.
- Affiliations
- Institute of Cancer Research (GB)
- University of Washington (US)
- European Bioinformatics Institute (GB)
- Wellcome Sanger Institute (GB)
- The University of Melbourne (AU)
- University of Pittsburgh (US)
- National Institutes of Health (US)
- Royal Marsden NHS Foundation Trust (GB)
- Corresponding author
- Allen, Sophie
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2024-03-04
- Volume
- 32
- Issue
- 5
- Pages
- 593-600
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- PMC
- PMC11061192
- OpenAlex
- W4392371883
- Cited by
- 17
- References
- 4
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 2
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- European Journal of Human Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Zenodo (CERN European Organization for Nuclear Research) (cc-by)
- Funders
- Cancer Research UK (EDDPGM-Nov22/100004, C61296/A27223)
- U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (RM1 HG01046, R01 HG013025)
- Wellcome Trust (WT223718/Z/21/Z)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (R01 HL164675)
- Gouvernement du Canada | Canadian Institutes of Health Research (FDN159926)
- U.S. Department of Health & Human Services | National Institutes of Health (HG200328-18, HG200359-15)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- MAVE, variants of uncertain significance, ClinVar, MaveDB, functional evidence, consensus recommendations
- MeSH terms
- Genetic Testing, Humans
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