Work

Genetic variant reclassification: a narrative review

Year: 2025

Type: review

Abstract: Objective A central challenge in clinical genetics lies in the precise interpretation of identified genetic variants and the effective communication of these findings to both patients and healthcare providers. Variability in the management of variant reclassifications, coupled with the absence of standardized guidelines for reevaluation, reanalysis, and the return of variant information, has introduced significant complexities into clinical practice. Although empirical studies have begun to address these issues, the scope and implications of this body of research remain insufficiently defined. Methods A systematic literature review was undertaken to examine research on variant reclassification within medical genetics in the last 10 years (until October 2025). Out of 582 unique records screened, 39 studies met inclusion criteria. These articles provide insights into the frequency and outcomes of variant reclassification. Results The included studies reported a wide rate of variant reclassification (from 3.6% to 83.6%). Nineteen studies (48.7%) focused on variants of uncertain significance (VUS), whereas the others included all variant types. The main fields were oncology and cardiology, only one study evaluated reclassification in patients living with obesity. Reclassification methods included literature review, functional studies, in silico prediction of pathogenicity, segregation analysis, and use of machine learning tools. Conclusions Several ongoing studies on variant reclassification have retrospectively applied established classification guidelines to previously reported variants, illustrating the potential volume of successful reclassifications achievable through routine reinterpretation and reanalysis. Identified research gaps include the limited understanding of the practices especially in the field of endocrinology and the need for structured deliberative processes to foster consensus on recontact and reclassification protocols.

Source: Obesity and Endocrinology

DOI: 10.1093/obendo/wjaf017