ArticleCancers2026
Risk Tier, Variant Certainty, and Real-World Care Patterns in Breast Cancer Patients with Germline Alterations in Breast Cancer Susceptibility Genes.
Article in Cancers, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundThe increasing use of multigene germline testing in breast cancer has expanded the detection of pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs) across a broad range of breast cancer susceptibility genes. However, the extent to which pathogenic certainty and penetrance level are associated with distinct clinicopathological phenotypes and management patterns remains incompletely defined.
methodsIn this multicenter retrospective study, we included 405 breast cancer patients with germline alterations in breast cancer susceptibility genes. Patients were classified into three groups: high-penetrance P/LP (
resultsPatients with high-penetrance P/LP variants were younger at diagnosis and had higher Ki-67 values than those in the other groups. Molecular subtype distribution differed significantly across groups, with triple-negative disease most frequent in the high-penetrance P/LP group (33.9%) compared with the moderate/low-penetrance P/LP (9.8%) and VUS (12.9%) groups. In multivariable analysis, high-penetrance P/LP status was independently associated with increased odds of non-luminal phenotype compared with VUS (OR 1.79, 95% CI 1.06-3.04;
conclusionsAmong breast cancer patients with germline alterations in breast cancer susceptibility genes, high-penetrance P/LP variants are associated with a distinct clinicopathological profile characterized by younger age at diagnosis, higher proliferative activity, and increased likelihood of non-luminal disease. In contrast, moderate/low-penetrance P/LP variants, especially VUSs, do not show the same degree of phenotype specificity. These findings support a framework in which pathogenic certainty and penetrance level remain central to the interpretation of multigene germline testing in breast cancer.
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