A Pilot Meta-Research on Evolving Evidence Behind Genetic Variant (Re)Classification.
Haotian Ma1, Zihan Xu1, Wendy Chung2
1Weill Cornell Medicine, New York, NY, US.
Studies in Health Technology and Informatics
|August 8, 2025
Summary
Reclassifying variants of uncertain significance (VUS) in BRCA1 and BRCA2 genes requires stronger evidence. This study found issues with citation accuracy and temporal alignment, highlighting the need for diverse data in genomic variant reclassification.
Area of Science:
- Genomic Medicine
- Clinical Genetics
- Bioinformatics
Background:
- Variant classification is crucial for precision medicine.
- Variants of Uncertain Significance (VUS) in BRCA1 and BRCA2 require careful reclassification.
- Current reclassification practices may have limitations.
Purpose of the Study:
- To evaluate the evidence supporting VUS reclassifications in BRCA1 and BRCA2.
- To assess the accuracy, completeness, and currency of cited publications for VUS reclassifications.
- To identify patterns and potential improvements in genomic variant reclassification.
Main Methods:
- Analysis of 162 unique cited publications supporting VUS reclassifications.
- Examination of citation accuracy, completeness, and temporal alignment.
- Review of cited studies for common themes like genetic mechanisms and computational tools.
Main Results:
- Inadequate or missing evidence was found for numerous VUS reclassifications.
- Temporal misalignment between citations and ClinVar submissions was observed.
- Cited studies often relied on classification recommendations, genetic mechanisms, computational tools, and population data.
Conclusions:
- There is a need for more robust evidence to support genomic variant reclassifications.
- Increased inclusion of diverse population data is essential for accurate VUS reclassification.
- Optimizing VUS reclassification will improve clinical decision-making in precision medicine.
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