Validation structures for sequence variants of uncertain significance in hereditary cancer

Hereditary cancer syndromes are among the most common inherited disorders and contribute to nearly 10% of solid tumours. While genetic testing is now central to diagnosis, surveillance, and cascade prevention, its impact is constrained by the persistent challenge of variants of uncertain significance (VUS), which comprise almost 40% of reported hereditary cancer syndrome-associated variants in ClinVar. These unresolved classifications undermine the interpretive power of testing, limiting its translational and preventive potential. In this review, we examine the foundations of variant interpretation, the role of expert-guided specifications, and emerging methods for VUS reclassification, including population-level data, RNA- and protein-based functional assays, computational predictors, and long-read sequencing. We further highlight how systematic re-evaluation structures and curation infrastructures translate new evidence into clinical practice. We conclude with an outlook on future directions to reduce the burden of VUS and increase the clinical utility of hereditary cancer syndrome testing.