From Expert Judgment to Structured Guidelines: A Brief History and Bright Future of DNA Variant Interpretation

Abstract

Background

The classification of sequence variants is at the core of human genetic diagnostics and is the basis for clinical guidance - incorrectly classified variants may cause great harm to patients and their families.

Methods

We provide an overview of the evolution of ideas and algorithms that have led to the formulation of elaborate classification systems over the last decades, culminating in the ACMG/AMP classification system. Furthermore, we address a still unsolved problem in the clinical translation of DNA analyses: variants of unclear significance (VUS).

Results

Rigorous data sharing and the sub-categorisation of VUS could facilitate a clearer interpretation of VUS.

Conclusion

This review underscores the efforts of the HUGO Education Committee to empower professional—sespecially in resource-limited settings—with the expertise needed for high-quality variant interpretation, fostering equitable access to the transformative potential of genomic medicine.