Penetrance of breast cancer genes from the eMERGE III Network

Fan X, Wynn J, Shang N, Liu C, Fedotov A, Hallquist MLG, Buchanan AH, Williams MS, Smith ME, Hoell C, Rasmussen-Torvik LJ, Peterson JF, Wiesner GL, Murad AM, Jarvik GP, Gordon AS, Rosenthal EA, Stanaway IB, Crosslin DR, Larson EB, Leppig KA, Henrikson NB, Williams JL, Li R, Hebbring S, Weng C, Shen Y [+], Crew KD [+], Chung W [+].

JNCI Cancer Spectrum, 2021.

Lab members marked as bold; [+] co-senior authors


We studied the penetrance and clinical outcomes of seven breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, ATM, PALB2 and PTEN) in almost 25,000 participants unselected for personal or family history of breast cancer. We identified 420 participants with pathogenic or likely pathogenic variants, and 147 were women who did not previously know their genetic results. Out of these 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 18-44%, depending on the gene. Within the first twelve months after genetic results disclosure, 42% of women had taken actions related to their genetic results and two new breast cancer cases were identified. Our study provides population-based penetrance estimates for the understudied genes, CHEK2, ATM, and PALB2, and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve healthcare through early diagnosis and preventative screening.

A preprint version of this manuscript is available at medRxiv: