American College of Medical Genetics and Genomics guidelines, alongside those from the Association for Molecular Pathology, were used to categorize variants, with only PVs reported. CHEK2 low-penetrance (CHEK2LP) variants were reported separately.
Personalized screening and data collection
Personalized screening assignments were provided to patients with PVs, and those in the personalized arm also received genotyping for single-nucleotide variants. Previous germline genetic testing, alongside testing results, were reported by participants through a baseline questionnaire. Those with positive results were categorized as aware of prior germline PV and excluded.
Self-reported demographic information, health information, and family breast and ovarian cancer history were also obtained from baseline questionnaires. Patients with family cancer history also reported each family member’s status separately, including age of onset, sex, and lineage.
There were 30,192 women in the personalized screening arm, 47.1% of whom were randomly assigned to this group and 52.9% of whom selected to be included. A mean age of 54.3 years was reported for patients who completed germline genetic testing, and 9.3% of participants identified as Hispanic, 0.3% as American Indian, 4.6% as Asian, 4.3% as Black, 77.3% as White, and 4% as multiracial or of another race.
Prevalence of PVs
Jewish ancestry was reported in 14.7% of patients, while a personal history of cancer besides breast cancer was reported in 13.5%. An overall PV detection of 2.6% was reported after exclusion of participants with awareness of prior PV. Being heterozygous for 2 different PVs was reported in 8 participants.
No personal cancer history was reported in the 5 women with TP53 PVs, with 4 not reporting any family history either. However, 1 reported a variety of cancers in multiple relatives. A personal history of gastric cancer was reported in 1 of 3 women with a CDH1 PV. There were no participants with a PTEN or STK11 PV reported.
PV rates did not significantly differ between self-selected vs randomly assigned patients, with rates of 2.8% and 2.4%, respectively. Characteristics linked to increased PV odds included younger age and European ancestry.
Impact of family history
In women with no breast or ovarian cancer history, a PV rate of 2.3% was reported vs 1.5% for high-penetrance and moderate-penetrance genes. These rates were increased in women with at least 2 relatives who had breast cancer, at 3.3% and 2.4%, respectively.
Of women receiving genetic testing, 14.7% had at least 1 grandparent with Jewish ancestry. When excluding those aware of their PV before joining the trial, this rate was 3.5%, with only 1.6% having PV in high-penetrance and moderate-penetrance genes. Overall, these results highlighted the efficacy of using genetic testing for breast cancer risk assessment.
“Our results demonstrate that relying on a reported family history of cancer has limitations in identifying women who carry a PV, and criteria-independent testing would broaden the group who could benefit from evidence-based cancer surveillance and risk-reduction interventions,” wrote investigators.
References
- Fergus KB, Ross KS, Scheuner MT, et al. Germline pathogenic variants among women without a history of breast cancer: a secondary analysis of the WISDOM randomized clinical trial. JAMA Intern Med. Published online December 12, 2025. doi:10.1001/jamainternmed.2025.7323
- Owens DK, Davidson KW, Krist AH, et al; US Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement. JAMA. 2019;322(7):652-665. doi:10.1001/jama.2019.10987
