Background: Germline pathogenic variants (PVs) in the moderate penetrance ATM gene confer a roughly 2-fold increased risk for breast cancer. Currently, any woman with an ATM PV meets the >20% lifetime risk threshold for consideration of relatively aggressive screening recommendations, which include initiating screening at younger ages and consideration of breast MRI. We and others have previously shown that breast cancer risks for women with inherited PVs in many hereditary breast cancer genes can be adjusted using PRS data, breast cancer family history, and other clinical information. Herein we show the development of a comprehensive breast cancer risk model for ATM PV carriers incorporating a previously described 86-variant PRS along with family history/clinical information captured by Tyrer-Cuzick V7.02. Methods: This IRB-approved study included de-identified clinical records from 353,809 women of European ancestry who were tested clinically for hereditary cancer risk with a multi-gene panel. Model development analyzed ATM PV carriers (N=2,666) and women negative for breast cancer gene PVs (N=351,143) who were tested between September 2013 and November 2019 (July 2019 for non-carriers). Women with the unusually high risk ATM c.7271 allele were excluded from analysis. Risk estimates incorporating ATM, PRS, and Tyrer-Cuzick were calculated using a fixed-stratified method that accounted for correlations between risk factors in a manner equivalent to multivariable co-estimation. Risk stratification was assessed in an independent cohort of ATM carriers (N=272) who were tested after November 2019 and were not included in model development. Results: We detected significant positive correlation of ATM status with breast cancer family history (p=1.6×10−7). Within ATM PV carriers, we observed positive yet non-significant (at alpha <0.05) correlation between PRS and breast cancer family history (p=0.10); joint effects were co-estimated using the fixed-stratified method. After adjusting for multiple testing, we found no evidence of interaction of ATM status with clinical factors, or PRS with clinical factors within ATM carriers. In an independent cohort, 30.1% of ATM carriers were categorized as having low breast cancer risk (<20%), 58.5% as moderate risk (20-50%), and 11.4% as high risk (>50%). Conclusions: In ATM PV carriers, our comprehensive model allowed for differentiation of ATM PV carriers into low, moderate, and high breast cancer risk categories. Precision breast cancer risk estimation may inform individualized clinical screening and prevention strategies.

Citation Format: Shannon Gallagher, Elisha Hughes, Eric Rosenthal, Allison W. Kurian, Susan Domchek, Judy Garber, Braden Probst, Brian Morris, Placede Tshiaba, Benjamin Roa, Thomas P. Slavin, Susanne Wagner, Jeffrey N. Weitzel, Alexander Gutin, Jerry S. Lanchbury, Mark E. Robson. Development of a breast cancer risk assessment model for ATM mutation carriers incorporating tyrer-cuzick and a polygenic risk score (PRS) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-09.