Ciyu Yang1, Angela G Arnold2, Amanda Catchings2, Vikas Rai1, Zsofia K Stadler2, Liying Zhang3,4. 1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. 2. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. 3. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. LiyingZhang@mednet.ucla.edu. 4. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA. LiyingZhang@mednet.ucla.edu.
Abstract
PURPOSE: Mutations in RAD51D are associated with a predisposition to primary ovarian, fallopian tube, and peritoneal carcinoma. Our study aims to characterize a RAD51D missense variant in a hereditary ovarian cancer family. METHODS: The effects of the RAD51D c.82G>A (p.Val28Met) variant on mRNA splicing were evaluated and characterized using RT-PCR, cloning and DNA sequencing. RESULTS: This variant completely disrupts normal splicing and results in the loss of 3'end of 5'UTR and the entire exon 1 (c.-86_c.82), which presumably leads to loss of the RAD51D protein. The RAD51D c.82G>A (p.Val28Met) variant is clinically significant and classified as likely pathogenic. CONCLUSIONS: Our results indicate that the RAD51D c.82G>A (p.Val28Met) variant contributes to cancer predisposition through disruption of normal mRNA splicing. The identification of this variant in an individual affected with high-grade serous fallopian tube cancer suggests that the RAD51D variant may contribute to predisposition to the ovarian cancer in this family.
PURPOSE: Mutations in RAD51D are associated with a predisposition to primary ovarian, fallopian tube, and peritoneal carcinoma. Our study aims to characterize a RAD51D missense variant in a hereditary ovarian cancer family. METHODS: The effects of the RAD51D c.82G>A (p.Val28Met) variant on mRNA splicing were evaluated and characterized using RT-PCR, cloning and DNA sequencing. RESULTS: This variant completely disrupts normal splicing and results in the loss of 3'end of 5'UTR and the entire exon 1 (c.-86_c.82), which presumably leads to loss of the RAD51D protein. The RAD51D c.82G>A (p.Val28Met) variant is clinically significant and classified as likely pathogenic. CONCLUSIONS: Our results indicate that the RAD51D c.82G>A (p.Val28Met) variant contributes to cancer predisposition through disruption of normal mRNA splicing. The identification of this variant in an individual affected with high-grade serous fallopian tube cancer suggests that the RAD51D variant may contribute to predisposition to the ovarian cancer in this family.
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