The RAD51D c.82G>A (p.Val28Met) variant disrupts normal splicing and is associated with hereditary ovarian cancer

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.

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Funding

This study was funded by Department of Pathology, Memorial Sloan Kettering Cancer Center.

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Correspondence to Liying Zhang.

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Z.K.S. reports that an immediate family member holds consulting/advisory roles with Allergan, Adverum, Genentech/Roche, Gyroscope Tx, Novartis, Neurogene, Optos Plc, Regeneron, Regenxbio. L.Z. reports honoraria (Future Technology Research LLC, BGI, Illumina); honoraria and Travel and accommodation expenses (Roche Diagnostics Asia Pacific). Family members hold leadership position and ownership interests of Decipher Medicine.

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Yang, C., Arnold, A.G., Catchings, A. et al. The RAD51D c.82G>A (p.Val28Met) variant disrupts normal splicing and is associated with hereditary ovarian cancer. Breast Cancer Res Treat 185, 869–877 (2021). https://doi.org/10.1007/s10549-020-06066-7

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Keywords

  • Ovarian cancer
  • RAD51D
  • Missense variant
  • Splicing