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

Abstract

IntroductionVariant-level functional data is a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUS). However, the usage of functional data by genetics professionals is currently unknown. MethodsAn online survey was developed and distributed in spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses. Results190 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 in assessing functional data. However, 67% indicated that functional data for variants of interest was rarely or never available, and 91% considered insufficient quality metrics or confidence in the accuracy of data as barriers to its 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. DiscussionThe results from this survey showed a demand for a comprehensive database with reliable quality metrics to support 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.