# Multiplexed functional analysis of BRCA1and BARD1 missense variants in DNA repair

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $523,369

## Abstract

Multiplexed functional analysis of BRCA1 and BARD1 missense variants in DNA repair
ABSTRACT
Variants of unknown significance (VUS) are, in general, missense variants for which the interpretation of
phenotypic impact is trapped in the void between pathogenic and benign. Any of these amino acid substitutions
could cause major damage to the structure or molecular function of the encoded protein and therefore
significantly impact disease risk, or it could have no effect all. Nowhere is the problem of VUS more apparent
than in genetic testing for hereditary breast and ovarian cancer where published VUS rates range from 2-42%
depending on the company doing testing/variant calling and number of genes included on the panel. For
BRCA1 alone, there are 1020 VUS listed in the clinical genetics database, ClinVar. To address the problem of
VUS interpretation, which is required to make genetic test results more useful for more patients, functional
assays could be used to understand how each variant affects protein function. However, performing a post hoc
functional assay for each variant as it is discovered is impossible at the current rate of accumulation. Here we
propose to use deep mutational scanning to determine the functional impact of all possible missense variants
in BRCA1 and BARD1 on their function in DNA repair in human cells. Our approach, developed in
collaboration between our labs at Ohio State University and the University of Washington, measures the
functional capacity of hundreds of protein variants in parallel in a homology directed DNA double strand break
repair assay. The outcome of this project will have two deliverables: The first is an understanding of the
sequence–function relationships, at single amino acid resolution, of two tumor suppressors in their role
protecting the genome from DNA double strand breaks. The second outcome is a “look up table” for the
functional impact of any possible missense variant in BRCA1 and BARD1 that can be used by clinical
geneticists to aid interpretation for variants that have been identified previously and those that have not yet
been seen in the clinic.

## Key facts

- **NIH application ID:** 9830634
- **Project number:** 5R01CA228083-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** JEFFREY D PARVIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $523,369
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830634

## Citation

> US National Institutes of Health, RePORTER application 9830634, Multiplexed functional analysis of BRCA1and BARD1 missense variants in DNA repair (5R01CA228083-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830634. Licensed CC0.

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