Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencing
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 t...
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Elsevier
2025-01-01
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| Series: | Genetics in Medicine Open |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2949774424010604 |
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| author | Youbao Sha J. Bryce Ortiz Sara L. Bristow Kate Loranger Linyan Meng Xiaonan Zhao Fan Xia Sheetal Parmar Adam C. ElNaggar Wenbo Xu |
| author_facet | Youbao Sha J. Bryce Ortiz Sara L. Bristow Kate Loranger Linyan Meng Xiaonan Zhao Fan Xia Sheetal Parmar Adam C. ElNaggar Wenbo Xu |
| author_sort | Youbao Sha |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-fc2da99887804a18b150c6abcdbaf5ea |
| institution | Kabale University |
| issn | 2949-7744 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Genetics in Medicine Open |
| spelling | doaj-art-fc2da99887804a18b150c6abcdbaf5ea2025-01-22T05:44:42ZengElsevierGenetics in Medicine Open2949-77442025-01-013101914Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencingYoubao Sha0J. Bryce Ortiz1Sara L. Bristow2Kate Loranger3Linyan Meng4Xiaonan Zhao5Fan Xia6Sheetal Parmar7Adam C. ElNaggar8Wenbo Xu9Natera, Inc. Austin, TXNatera, Inc. Austin, TXNatera, Inc. Austin, TXNatera, Inc. Austin, TXBaylor Miraca Genetics Laboratories, LLC, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TXBaylor Miraca Genetics Laboratories, LLC, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TXBaylor Miraca Genetics Laboratories, LLC, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TXNatera, Inc. Austin, TXNatera, Inc. Austin, TXNatera, Inc. Austin, TX; Correspondence and requests for materials should be addressed to Wenbo Xu, Natera, Inc, 13011A McAllen Pass, Austin, TX 78753.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.http://www.sciencedirect.com/science/article/pii/S2949774424010604Hereditary cancerPathogenic variantsRNA sequencingVariants of uncertain significance |
| spellingShingle | Youbao Sha J. Bryce Ortiz Sara L. Bristow Kate Loranger Linyan Meng Xiaonan Zhao Fan Xia Sheetal Parmar Adam C. ElNaggar Wenbo Xu Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencing Genetics in Medicine Open Hereditary cancer Pathogenic variants RNA sequencing Variants of uncertain significance |
| title | Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencing |
| title_full | Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencing |
| title_fullStr | Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencing |
| title_full_unstemmed | Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencing |
| title_short | Refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated RNA sequencing |
| title_sort | refining the interpretation of variants of uncertain significance in hereditary cancer screening through integrated rna sequencing |
| topic | Hereditary cancer Pathogenic variants RNA sequencing Variants of uncertain significance |
| url | http://www.sciencedirect.com/science/article/pii/S2949774424010604 |
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