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Validation structures for sequence variants of uncertain significance in hereditary cancer

European Journal of Human Genetics (2026)Cite this article

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Abstract

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.

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Acknowledgements

The authors thank the team at the Medizinisch Genetisches Zentrum (MGZ), Munich for their valuable discussions and support. Figures were created with BioRender.com. The authors also acknowledge the constructive feedback from colleagues within the hereditary cancer research community, which helped refine the focus and clarity of this review.

Funding

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Author notes

  1. These authors contributed equally: Morghan C. Lucas, Thomas Keßler.

Authors and Affiliations

  1. MGZ – Medical Genetics Center, Munich, Germany

    Morghan C. Lucas, Thomas Keßler, Anna Benet-Pagès, Elke Holinski-Feder, Andreas Laner & Barbara Klink

  2. Medizinische Klinik und Poliklinik IV – Campus Innenstadt, Klinikum der Universität München, Munich, Germany

    Morghan C. Lucas, Elke Holinski-Feder & Barbara Klink

  3. Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich, Germany

    Anna Benet-Pagès

  4. Genturis European Reference Network (ERN) Genetic Tumor Risk (GENTURIS), Nijmegen, Netherlands

    Elke Holinski-Feder & Barbara Klink

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MCL and TK contributed equally to the conception and design of the review. ABP, EHF, AL, and BK provided critical input, references, and revisions. All authors discussed the content, revised the manuscript for important intellectual content, and approved the final version for submission.

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Correspondence to Morghan C. Lucas or Barbara Klink.

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Lucas, M.C., Keßler, T., Benet-Pagès, A. et al. Validation structures for sequence variants of uncertain significance in hereditary cancer. Eur J Hum Genet (2026). https://doi.org/10.1038/s41431-026-02073-2

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