Germline Pathogenic Variants Among Women Without a History of Breast Cancer: A Secondary Analysis of the WISDOM Randomized Clinical Trial

Among 23 098 women who completed germline genetic testing (mean age, 54.3 years), 714 (3.1%) carried a PV. Excluding 109 who were previously aware of their PV, the detection rate was 2.6%. PVs were most common in CHEK2 (337) and ATM (101) but less common in higher-penetrance genes (BRCA1, 33; BRCA2, 82; PALB2, 44). PVs in the CDH1, PTEN, STK11, and TP53 genes were rare (less than 0.1%). Notably, 180 of 605 women with PVs (29.8%) did not report a first-degree or second-degree female relative with breast or ovarian cancer, male relative with breast cancer, or Jewish ancestry. In this secondary analysis of the WISDOM trial, criteria-independent genetic testing identified a substantial number of women with clinically actionable results, many of whom would not have qualified for genetic testing under current guidelines. These findings support broader access to genetic testing as part of personalized breast cancer risk assessment.