# 01 Project 1:  Cancer risks for mutations in breast cancer predisposition genes

> **NIH NIH P50** · MAYO CLINIC ROCHESTER · 2021 · $80,648

## Abstract

PROJECT SUMMARY 
Breast cancer is one of the most common cancers in the US. Approximately 15% to 20% of cases exhibit a 
family history of the disease suggesting a strong heritable component. Susceptibility to breast cancer is 
associated with high-penetrance germline mutations in BRCA1, BRCA2, PTEN, STK11, CDH1, and TP53. In 
addition, inherited inactivating mutations in several other genes have been associated with familial breast 
cancer. These include ATM, CHEK2, PALB2, BRIP1, BARD1, RAD51C, RAD51D, XRCC2, NBN, RAD50, and 
MRE11A. While inactivating mutations in ATM and CHEK2 have been associated with moderate 3 to 7-fold 
increased risk of breast cancer with lifetime risks of between 20% and 50%, these risk estimates are imprecise 
and little is known about the risk of breast and other cancers associated with inactivating mutations in other 
predisposition genes. Clinical genetic testing for all of these high and moderate risk predisposition genes is 
now available. Many women, with personal and family history of breast, ovarian or other cancers, are pursuing 
testing for mutations with these panels, which has seen an upsurge in demand in response to `Angelina's 
story'. Initial data suggest that ~10% of panel tests identify truncating mutations and 20% yield variants of 
uncertain significance (VUS) in the form of missense and intronic changes of undefined clinical relevance in 
the known predisposition genes. Although potentially useful for establishing the etiology of breast cancer in a 
family, there remain significant limitations in the clinical interpretation of the results from the panel testing. In 
particular, the age-related risk of breast and other cancers associated with pathogenic mutations in the genes 
are largely undefined. Furthermore, clear age-related medical management recommendations have not been 
developed. Thus, the results of these tests can lead to confusion and uninformed medical decisions that can 
result in significant harm. Here we propose to establish the risks of breast and other cancers associated with 
pathogenic mutations and to classify the clinical relevance of VUS in known breast cancer predisposition genes 
using family based registry studies, along with functional and pathology studies as follows: Aim 1) Define the 
penetrance of cancers associated with inactivating mutations in panel-based predisposition genes; Aim 2) 
Determine the clinical relevance of VUS in panel-based known predisposition genes; Aim 3) Assess clinical- 
pathological features of mutations in cancer predisposition genes. At the conclusion of this population 
sciences-based study, improved risk assessment based on the risk estimates associated with pathogenic 
mutations in these genes, methods for establishing the clinical relevance of many VUS in the known 
predisposition genes, and data for establishing medical management recommendations for carriers of 
mutations in predisposition genes will be available.

## Key facts

- **NIH application ID:** 10492092
- **Project number:** 3P50CA116201-15S1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Fergus Joseph Couch
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $80,648
- **Award type:** 3
- **Project period:** 2005-09-22 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492092

## Citation

> US National Institutes of Health, RePORTER application 10492092, 01 Project 1:  Cancer risks for mutations in breast cancer predisposition genes (3P50CA116201-15S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10492092. Licensed CC0.

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