ArticleGenetics in medicine open2025
Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencing.
Article in Genetics in medicine open, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Rapid minigene workflow for functional reclassification of splicing variants in hereditary cancer diagnostics.Journal of medical genetics · 2026Article
- When splicing is not all or none: GT>GC 5' splice-site variants as a model for intermediate effects and challenges in variant classification.HGG advances · 2026Article
- Variant-specific RNA testing resolves variants of uncertain significance in exome testing.BMC genomics · 2026Article
- Targeted reflex RNA sequencing for enhanced variant classification on exome and genome sequencing improves patient outcomes.NPJ genomic medicine · 2026Article
- A machine learning framework for predictive interpretation of variants of uncertain significance in hereditary cancer.Frontiers in systems biology · 2026Article
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Purpose: Although up to 25% of germline variants are predicted to affect splicing, most are classified as variants of uncertain significance (VUS) because of the limited understanding of their functional consequences. Here, we investigated the impact of RNA sequencing (RNA-seq) data on the ability to resolve splicing-related VUS. Methods: Patients with VUS predicted to alter splicing identified through commercial hereditary cancer testing between October 2021 to July 2023 were included. RNA-seq was used to compare splicing patterns between patient blood samples and normal controls. VUS reclassification rates were calculated. Results: In total, 411 VUS in 52 genes predicted to affect splicing were included. RNA-seq results resolved 26.3% (108/411) of the VUS: 28 (6.8%) upgraded to pathogenic/likely pathogenic, and 80 (19.5%) downgraded to not reportable. Among the 28 upgraded, 17 (60.7%) were intronic, 9 (32.1%) were exonic missense variants, and 2 (7.1%) were exonic synonymous variants. Most of the VUS downgraded to not reportable were intronic (64/80, 80%). The remaining 16 (20%) of the downgraded VUS were synonymous variants. Conclusion: This study underscores the utility of RNA-seq to detect variants that affect splicing and could have an impact on cancer risk assessment management and treatment.
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