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Review

Imprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules

1
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA
2
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Shailja Pathania
Genes 2021, 12(5), 780; https://doi.org/10.3390/genes12050780
Received: 28 April 2021 / Revised: 14 May 2021 / Accepted: 18 May 2021 / Published: 20 May 2021
(This article belongs to the Special Issue BRCA1 and BRCA2: Genome Instability and Tumorigenesis)
Pathological mutations in homology-directed repair (HDR) genes impact both future cancer risk and therapeutic options for patients. HDR is a high-fidelity DNA repair pathway for resolving DNA double-strand breaks throughout the genome. BRCA2 is an essential protein that mediates the loading of RAD51 onto resected DNA breaks, a key step in HDR. Germline mutations in BRCA2 are associated with an increased risk for breast, ovarian, prostate, and pancreatic cancer. Clinical findings of germline or somatic BRCA2 mutations in tumors suggest treatment with platinum agents or PARP inhibitors. However, when genetic analysis reveals a variant of uncertain significance (VUS) in the BRCA2 gene, precision medicine-based decisions become complex. VUS are genetic changes with unknown pathological impact. Current statistics indicate that between 10–20% of BRCA sequencing results are VUS, and of these, more than 50% are missense mutations. Functional assays to determine the pathological outcome of VUS are urgently needed to provide clinical guidance regarding cancer risk and treatment options. In this review, we provide a brief overview of BRCA2 functions in HDR, describe how BRCA2 VUS are currently assessed in the clinic, and how genetic and biochemical functional assays could be integrated into the clinical decision process. We suggest a multi-step workflow composed of robust and accurate functional assays to correctly evaluate the potential pathogenic or benign nature of BRCA2 VUS. Success in this precision medicine endeavor will offer actionable information to patients and their physicians. View Full-Text
Keywords: BRCA2; variants of uncertain significance; DNA repair; homologous recombination; hereditary breast and ovarian cancer (HBOC); BRCAness BRCA2; variants of uncertain significance; DNA repair; homologous recombination; hereditary breast and ovarian cancer (HBOC); BRCAness
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MDPI and ACS Style

Jimenez-Sainz, J.; Jensen, R.B. Imprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules. Genes 2021, 12, 780. https://doi.org/10.3390/genes12050780

AMA Style

Jimenez-Sainz J, Jensen RB. Imprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules. Genes. 2021; 12(5):780. https://doi.org/10.3390/genes12050780

Chicago/Turabian Style

Jimenez-Sainz, Judit, and Ryan B. Jensen. 2021. "Imprecise Medicine: BRCA2 Variants of Uncertain Significance (VUS), the Challenges and Benefits to Integrate a Functional Assay Workflow with Clinical Decision Rules" Genes 12, no. 5: 780. https://doi.org/10.3390/genes12050780

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