Risk Tier, Variant Certainty, and Real-World Care Patterns in Breast Cancer Patients with Germline Alterations in
Tuba Baydaş1, İlker Nihat Ökten1, Filiz Özen2
1Department of Medical Oncology, Göztepe Prof. Dr. Süleyman Yalçın City Hospital, Istanbul 34722, Türkiye.
Cancers
|May 27, 2026
Summary
High-penetrance pathogenic/likely pathogenic (P/LP) variants in breast cancer susceptibility genes are linked to younger diagnoses and non-luminal tumors. Moderate/low-penetrance P/LP variants and variants of uncertain significance (VUSs) show less specific phenotypes.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Multigene germline testing is increasingly used for breast cancer, identifying pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs).
- The association between variant penetrance, clinicopathological features, and management strategies requires further clarification.
Purpose of the Study:
- To investigate the relationship between the certainty and penetrance of germline alterations and breast cancer phenotypes and management.
- To compare clinicopathological features and treatment patterns across different categories of germline variants.
Main Methods:
- Retrospective analysis of 405 breast cancer patients with germline alterations.
- Classification into high-penetrance P/LP, moderate/low-penetrance P/LP, and VUS groups.
- Assessment of non-luminal invasive breast cancer phenotype (HER2-positive or triple-negative) and management patterns using multivariable logistic regression.
Main Results:
- High-penetrance P/LP variants were associated with younger age at diagnosis and higher Ki-67 values.
- Triple-negative disease was most frequent in the high-penetrance P/LP group (33.9%).
- High-penetrance P/LP status independently predicted a non-luminal phenotype (OR 1.79), unlike moderate/low-penetrance P/LP variants or VUSs. Management, including mastectomy rates, differed significantly across groups.
Conclusions:
- High-penetrance P/LP variants define a distinct breast cancer profile, including younger age, higher proliferation, and non-luminal subtypes.
- Moderate/low-penetrance P/LP variants and VUSs exhibit less specific clinicopathological associations.
- Pathogenic certainty and penetrance level are crucial for interpreting multigene germline test results in breast cancer.
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