# Elucidating Cancer Risk in BRCA2 and RAD51 Variants

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $383,156

## Abstract

PROJECT SUMMARY
The new era of precision medicine to discover and act upon genetic findings has inadvertently created a huge
clinical dilemma when a variant of uncertain significance (VUS) is encountered. Patients identified as BRCA or
RAD51 VUS carriers undergoing genetic counseling experience confusion, anxiety, and the potential for
misguided treatment plans. Current estimates indicate that between 10-20% of BRCA sequencing results are
VUS representing thousands of patients in the U.S. alone. These numbers will likely escalate as precision
medicine and commercially available genetic testing services are being deployed at a rapid pace. The BRCA2
and RAD51 proteins play central roles in the homology-directed repair (HDR) of DNA double-strand breaks
(DSBs). Functional diagnostic tools to decipher HDR VUS are still lacking in the setting of medical oncology.
This is a critical issue as germline HDR mutations predispose individuals to a high risk for cancer while somatic
mutations identified in tumors can dramatically impact treatment plans. For example, synthetic lethal strategies
employing PARP inhibitors are currently being exploited in oncology to selectively target HDR deficient tumors.
Therefore, the correct interpretation of a somatic tumor VUS can guide therapy selection. Functional assays to
determine the pathological outcome of VUS are urgently needed to provide clinical guidance regarding cancer
risk and treatment options. Our long-term objective is to bring molecular and mechanistic clarity to the
operative pathways that HDR utilizes to repair DNA breaks. By using a highly synergistic biochemical and
genetic approach, we aim to elucidate how VUS impact BRCA2 and RAD51 functions. Our central hypothesis
is that a cell-based and biochemical functional approach will successfully differentiate pathogenic from
harmless HDR VUS. In aim 1, we will establish cell-based complementation assays from which clinically
relevant agents can be used to identify pathogenic BRCA2 and RAD51 variants. Integrating tumor-derived
somatic variants into our cell-based models will enable in vitro testing of second-line therapies or novel
compounds informing clinical practice of patients who could derive benefit from targeted agents. In aim 2, we
will determine how pathogenic variants alter the biochemical functions of BRCA2 and RAD51. Results will be
used to further refine our mechanistic understanding of pathological HDR variants and how biochemical
defects translate into increased cancer risk. Our approach is innovative because of our unique skill set and
development of robust cell-based and biochemical functional assays to dissect HDR mechanisms focused on
BRCA2 and RAD51. The proposed research is significant because it will lay the groundwork to provide
patients and physicians with clinically actionable information regarding risk reduction steps and stratification for
targeted therapies such as PARP inhibitors. Furthermore, studies of pathological variants wil...

## Key facts

- **NIH application ID:** 10127591
- **Project number:** 5R01CA215990-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ryan Brown Jensen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,156
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10127591

## Citation

> US National Institutes of Health, RePORTER application 10127591, Elucidating Cancer Risk in BRCA2 and RAD51 Variants (5R01CA215990-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10127591. Licensed CC0.

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