Insights on improving accessibility and usability of functional data to unlock their potential for variant interpretation

Park, MS; Kumar, RD; Ovadiuc, C; Folta, A; McEwen, AE; Snyder, A; Villani, RM; Spurdle, AB; Fowler, DM; Rubin, AF; Shirts, BH; Starita, LM; Stergachis, AB

Author(s): Park, MS; Kumar, RD; Ovadiuc, C; Folta, A; McEwen, AE; Snyder, A; Villani, RM; Spurdle, AB; Fowler, DM; Rubin, AF; Shirts, BH; Starita, LM; Stergachis, AB;
Details: Publication Year 2025-06-05,Volume 112,Issue #6,Page 1468-1478
Journal Title: American Journal of Human Genetics
Abstract: Variant-level functional data are a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUSs). However, the usage of functional data by genetics professionals is currently unknown. An online survey was developed and distributed in the spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses. 190 eligible individuals responded, with 93% reporting interpreting 26 or more variants per year. The median respondent reported 11-20 years of experience. The most common professional roles were laboratory medical geneticists (23%) and variant review scientists (23%). 77% reported using functional data for variant interpretation in a clinical setting, and overall, respondents felt confident assessing functional data. However, 67% indicated that functional data for variants of interest were rarely or never available, and 91% considered insufficient quality metrics or confidence in the accuracy of data as barriers to their use. 94% of respondents noted that better access to primary functional data and standardized interpretation of functional data would improve usage. Respondents also indicated that handling conflicting functional data is a common challenge in variant interpretation that is not performed in a systematic manner across institutions. The results from this survey showed a demand for a comprehensive database with reliable quality metrics to support the use of functional evidence in clinical variant interpretation. The results also highlight a need for guidelines regarding how putatively conflicting functional data should be used for variant classification.
Publisher: Cell Press
Keywords: Humans; *Genetic Variation/genetics; Surveys and Questionnaires; Male; Female; Genetic Testing; Adult; Mave; functional data; multiplexed assays for variant effect; survey; variant classification
Research Division(s): Bioinformatics and Computational Biology
PubMed ID: 40480199
Publisher's Version: https://doi.org/10.1016/j.ajhg.2025.04.009
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-06-26 09:55:24

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