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

Villani, RM; Terrill, B; Tudini, E; McKenzie, ME; Cliffe, CC; Hahn, CN; Lundie, B; Mattiske, T; Matotek, E; McEwen, AE; Nickerson, SL; Breen, J; Fowler, DM; Christodoulou, J; Starita, L; Rubin, AF; Spurdle, AB

Author(s): Villani, RM; Terrill, B; Tudini, E; McKenzie, ME; Cliffe, CC; Hahn, CN; Lundie, B; Mattiske, T; Matotek, E; McEwen, AE; Nickerson, SL; Breen, J; Fowler, DM; Christodoulou, J; Starita, L; Rubin, AF; Spurdle, AB;
Details: Publication Year 2025-06-05,Volume 112,Issue #6,Page 1489-1495
Journal Title: American Journal of Human Genetics
Abstract: When 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.
Publisher: Cell Press
Keywords: Humans; *Genetic Testing/methods; *Genetic Variation/genetics; *Referral and Consultation; Surveys and Questionnaires; ACMG/AMP guidelines; assay; clinical genomics; diagnostic genetics; education; functional evidence; pathogenicity assessment; variant classification
Research Division(s): Bioinformatics and Computational Biology
PubMed ID: 40480201
Publisher's Version: https://doi.org/10.1016/j.ajhg.2025.05.003
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-06-26 09:55:32

Last Modified: 2025-06-26 09:56:13