Abstract RF5-04: Germline pathogenic variants in the personalized screening arm of the WISDOM Study: Findings from 23,098 women with no personal history of breast cancer

Abstract Background: The population prevalence of pathogenic variants (PVs) in breast cancer susceptibility genes (BCSG’s) remains largely unknown, in part due to restrictions in genetic testing guidelines. We report early BCSG prevalence estimates from the Women Informed to Screen Depending on Measures of Risk (WISDOM) Trial, where women in the personalized screening arm were offered unrestricted genetic testing, and evaluate the relationship of test positivity to family history and other patient characteristics. Methods: The WISDOM Trial enrolled women without breast cancer between 2016-2023 aged 40-74 in a pragmatic randomized screening trial comparing annual screening mammography to personalized risk-based screening. Participants in the personalized arm were offered germline testing for nine breast cancer susceptibility genes (BRCA1, BRCA2, ATM, CHEK2, PALB2, CDH1, PTEN, STK11, TP53). We report the prevalence of PVs in the trial and the distribution of self-reported demographic and family history data in the sub-population with PVs. Results: Among 23,098 participants who enrolled in the trial and completed genetic testing, 714 (3.1%) carried a PV. After excluding those previously aware of their PV, the detection rate was 2.6%. PVs were most common in CHEK2 (1.47%) and less common in higher-penetrance BRCA1 (0.14%), BRCA2 (0.36%), and PALB2 (0.19%) variants. PVs in the CDH1, PTEN, STK11, and TP53 genes were rare (