Reclassifying BRCA1 c.4358-2A > G and BRCA2 c.475 + 5G > C variants from "Uncertain Significance" to "Pathogenic" based on minigene assays and clinical evidence

根据微基因检测和临床证据,将 BRCA1 c.4358-2A > G 和 BRCA2 c.475 + 5G > C 变体从“意义不明确”重新分类为“致病”

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作者:Ying Ning #, Yu Zhang #, Tian Tian, Yu Chen, Jia Wang, Ke Lei, Zhumei Cui

Background

Pathogenic variants in BRCA genes play a crucial role in the pathogenesis of ovarian cancer. Intronic variants of uncertain significance (VUS) may contribute to pathogenicity by affecting splicing. Currently, the significance of many intronic variants in BRCA has not been clarified, impacting patient treatment strategies and the management of familial cases. Method: A retrospective study was conducted to analyze BRCA intronic VUS in a cohort of 707 unrelated ovarian cancer patients at a single institution from 2018 to 2023. Three splicing predictors were employed to analyze detected intronic VUS. Variants predicted to have splicing alterations were selected for further validation through minigene assays. Patient and familial investigations were conducted to comprehend cancer incidence within pedigrees and the application of poly (ADP-ribose) polymerase inhibitors (PARPi) by the patients. In accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG), the intronic VUS were reclassified based on minigene assay

Conclusion

Two intronic VUS were reclassified as pathogenic variants. A precise classification of variants is crucial for the effective treatment and management of both patients and healthy carriers.

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