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Consultation informs strategies for improving the use of functional evidence in variant classification

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dc.contributor.authorVillani, R.M.
dc.contributor.authorTerrill, B.
dc.contributor.authorTudini, E.
dc.contributor.authorMcKenzie, M.E.
dc.contributor.authorCliffe, C.C.
dc.contributor.authorHahn, C.N.
dc.contributor.authorLundie, B.
dc.contributor.authorMattiske, T.
dc.contributor.authorMatotek, E.
dc.contributor.authorMcEwen, A.E.
dc.contributor.authorNickerson, S.L.
dc.contributor.authorBreen, J.
dc.contributor.authorFowler, D.M.
dc.contributor.authorChristodoulou, J.
dc.contributor.authorStarita, L.
dc.contributor.authorRubin, A.F.
dc.contributor.authorSpurdle, A.B.
dc.date.issued2025
dc.description.abstractWhen investigating whether a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Functional assays of higher and higher throughput are increasingly being generated and, when appropriate, can provide strong functional evidence for or against pathogenicity in variant classification. Despite functional assay data representing unprecedented value for genomic diagnostics, challenges remain around the application of functional evidence in variant curation. To investigate a growing gap articulated in recent international studies, we surveyed genetic diagnostic professionals in Australasia to assess their application of functional evidence in clinical practice. The survey results echo the universal difficulty in evaluating functional evidence but expand on this by indicating that even self-proclaimed expert respondents are not confident to apply functional evidence, mainly due to uncertainty around practice recommendations. Respondents also identified the need for support resources and educational opportunities, and in particular requested expert recommendations and updated practice guidelines to improve translation of experimental data to curation evidence. We then collated a list of 226 functional assays and the evidence strength recommended by 19 ClinGen Variant Curation Expert Panels. Specific assays for more than 45,000 variants were evaluated, but evidence recommendations were generally limited to lower throughput and strength. As an initial step, we provide our collated list of assay evidence as a source of international expert opinion on the evaluation of functional- evidence and conclude that these results highlight an opportunity to develop additional support resources to fully utilize functional evidence in clinical practice.
dc.description.statementofresponsibilityRehan M. Villani, Bronwyn Terrill, Emma Tudini, Maddison E. McKenzie, Corrina C. Cliffe, Christopher N. Hahn, Ben Lundie, Tessa Mattiske, Ebony Matotek, Abbye E. McEwen, Sarah L. Nickerson, James Breen, Douglas M. Fowler, John Christodoulou, Lea Starita, Alan F. Rubin, and Amanda B. Spurdle
dc.identifier.citationAmerican Journal of Human Genetics, 2025; 112(6):1489-1495
dc.identifier.doi10.1016/j.ajhg.2025.05.003
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.orcidHahn, C.N. [0000-0001-5105-2554]
dc.identifier.orcidBreen, J. [0000-0001-6184-0925]
dc.identifier.urihttps://hdl.handle.net/2440/147557
dc.language.isoen
dc.publisherCell Press
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/177524
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1113531
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT2000001
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT2035846
dc.rights© 2025 American Society of Human Genetics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
dc.source.urihttps://doi.org/10.1016/j.ajhg.2025.05.003
dc.subjectfunctional evidence; variant classification; diagnostic genetics; education; assay; clinical genomics; ACMG/AMP guidelines; pathogenicity assessment
dc.subject.meshHumans
dc.subject.meshReferral and Consultation
dc.subject.meshGenetic Variation
dc.subject.meshGenetic Testing
dc.subject.meshSurveys and Questionnaires
dc.titleConsultation informs strategies for improving the use of functional evidence in variant classification
dc.typeJournal article
pubs.publication-statusPublished

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