Bold shift in how we assess breast cancer risk: genetic insights are personalizing care, yet uncertainties in variant classification linger.
Genetic risk models and variant interpretation tools are refining risk assessment—pinpointing individuals who need intensified surveillance or targeted therapies, while guiding those at moderate to lower risk toward personalized, less aggressive management. Although these tools are advancing, more research is needed to perfect their guidance.1
Experts explored these themes in an afternoon educational session at the San Antonio Breast Cancer Symposium, titled “Management for Predisposition Gene Carriers.”
How Genetic Risk Models Are Redefining Breast Cancer Risk Assessment
Tuya Pal, MD, from Vanderbilt University Medical Center, outlined how risk models predict the presence of germline pathogenic or likely pathogenic variants. She discussed multiple tools, including PREMMplus, which estimates the probability of carrying variants in 19 genes (about half of which are linked to breast cancer). A PREMMplus score of 2.5% or higher flags the need for multi-gene panel testing. In contrast, guidelines from the National Comprehensive Cancer Network (NCCN) suggest testing for high-penetrance breast cancer genes based on personal and family history, typically using a 5% or greater risk threshold across models like PREMMplus and Tyrer-Cuzick.
Pal emphasized that precise risk estimation guides clinical decisions. She defined lifetime risk categories as low (<20%), moderate (20–40%), and high (>40%). Moderate risk usually warrants enhanced screening (including MRI), while high-risk individuals may consider risk-reducing surgeries such as mastectomy. She also pointed out that guidelines for MRI screening or preventive surgeries vary by country and institution and may rely on outdated thresholds. She argued that 5- and 10-year risk estimates can be more informative than lifetime risk alone.
When comparing major risk models—Gail, Breast Cancer Surveillance Consortium Risk Calculator, BOADICEA/CanRisk, and Tyrer-Cuzick—Pal noted that incorporating genetic status and polygenic risk scores (PRS) can significantly shift risk estimates, sometimes inflating or reducing the perceived risk. Among these, BOADICEA/CanRisk and Tyrer-Cuzick include genetic information; BOADICEA, particularly when integrated with PRS, tends to be more accurate. CanRisk, built on the BOADICEA framework, combines genetic results, PRS, breast density, personal factors, and family history. Yet Pal cautioned that no model is perfect.
“Models give us a comparative sense of risk relative to the general carrier population, but we shouldn’t take the numbers as absolute,” Pal remarked.
She then highlighted emerging complexities in risk prediction, noting a shift from a binary view (mutation present or absent) to a continuum of risk. Some BRCA1/2 variants once labeled pathogenic are now recognized as lower-penetrance, creating interpretive challenges. Pal stressed the importance of distinguishing hypomorphic variants (reduced gene function) from reduced-penetrance pathogenic variants (lower clinical risk), since clinical relevance does not always translate to treatment response.
Through case examples, Pal demonstrated how risk models can overestimate risk when lower-penetrance variants are treated as typical mutations. She also showed how PRS, breast density, and family history can modify risk for moderate-penetrance genes like ATM or CHEK2; in certain families, strong modifying factors can push these variants into high-risk territory.
Her takeaway: breast cancer risk prediction is becoming more nuanced and individualized. “As we refine risks, the goal is to shrink the uncertainty bucket and produce tighter confidence intervals, improving our risk estimates. I don’t believe we’ll achieve perfection, but the trend is toward increasing precision,” she said. “More than ever, communicating these evolving risks effectively will be crucial.”
What Hurdles Remain in Understanding and Classifying Breast Cancer Gene Variants?
Fergus J. Couch, PhD, from Mayo Clinic, expanded on Pal’s overview by demystifying variant classification. He focused on high-risk genes (BRCA1, BRCA2, PALB2), moderate-risk genes (CHEK2, ATM), and ultra-rare genes just beginning to be characterized. Cancer risk from these genes varies—from about 70% lifetime risk for BRCA1/2 mutations to around 20% for some moderate-penetrance genes, with ultra-rare variants still poorly understood.
Couch outlined key variant types: nonsense and frameshift mutations typically disrupt protein function and are highly penetrant; consensus splice sites and nearby intronic variants can have unpredictable effects; copy number variants carry less clearly defined risk. However, missense variants often become variants of uncertain significance (VUS), leaving clinicians and patients without clear guidance.
“VUS are changes found in germline testing where we’re not sure what they mean for disease,” Couch explained. “They’re a major challenge in clinical practice, so much of our work is to determine which ones are real and which aren’t.”
He stressed that VUS should not drive patient management. Instead, decisions should rely on personal and family history unless a variant is reclassified with strong evidence. Common methods to interpret VUS include analyzing how the variant segregates in families, checking population frequency, using computational predictions, and performing functional assays. Following ACMG guidelines, these inputs combine to assign pathogenicity scores that estimate the likelihood a variant causes disease.
A notable advance is large-scale high-throughput functional studies using CRISPR/Cas9 in haploid cells, which test every possible variant in a gene region for effects on cell viability and protein function. Recent work has graded thousands of variants, effectively distinguishing pathogenic changes from benign ones. For example, a BRCA2 domain showed that 14% of missense variants behaved as strong pathogenic alleles, even though most appeared benign in clinical observations. This underscores the complexity beyond what clinical history alone reveals.
Integrating functional assay results into ACMG workflows can dramatically cut down the number of unresolved VUS. In Couch’s experience, over 90% of tested variants can be confidently classified, leaving only a small fraction undecided. Still, results can vary between experiments or laboratories, with discrepancies in roughly 20–25% of variants, so cross-validation remains essential.
“Progress in this field is rapid, but we need broader validation and dedicated variant curation expert panels to ensure consistent classification,” Couch concluded.
How Hereditary Breast Cancer Is Managed
Stephanie M. Wong, MD, MPH, from McGill University, reviewed evolving strategies for hereditary breast cancer care, focusing on BRCA1/2 and PALB2 carriers. For BRCA1/2 carriers diagnosed with breast cancer, options include breast-conserving therapy or bilateral mastectomy. While older retrospective studies showed no clear survival advantage for mastectomy, newer data suggest a potential survival benefit for bilateral mastectomy, particularly in carriers under 40. Contralateral breast cancer risk is highly dependent on age and gene, and because overall survival benefits remain mixed, guidelines advocate personalized counseling and patient preference in surgical choices.
In systemic therapy, BRCA-associated tumors often show homologous recombination repair deficiency, making them highly responsive to DNA-damaging agents and PARP inhibitors. Drugs like olaparib (Lynparza) and talazoparib (Talzenna) have shown meaningful benefits in metastatic settings and in high-risk, early-stage BRCA-mutated cases (per the OlympiA trial). There is also evidence supporting PARP inhibitors for PALB2-mutated metastatic breast cancer. Emerging data suggest combining PARP inhibitors with immunotherapy appears safe.
Wong also discussed moderate-penetrance carriers (ATM, CHEK2). These individuals generally have lower contralateral breast cancer risk, and current guidelines usually do not recommend routine risk-reducing mastectomy. Instead, decisions should be guided by family history, personal risk factors, and patient preferences, with individualized counseling. Adjuvant radiation is considered safe for ATM carriers based on growing evidence of low radiotoxicity.
Looking ahead, ongoing research aims to optimize treatment management, including endocrine prevention trials for moderate-penetrance carriers and exploring delayed oophorectomy strategies in BRCA carriers. Wong closed with appreciation for the remarkable progress in hereditary breast cancer care, much of it driven by researchers, clinicians, and engaged patients.
References
- Domchek S, Pal T, Couch FJ, Wong SM, Wedley-Majsiak B. Management for predisposition gene carriers. San Antonio Breast Cancer Symposium 2025, December 9–12, 2025, San Antonio, Texas.
- Olaparib as adjuvant treatment in patients with germline BRCA mutated high risk HER2-negative primary breast cancer (OlympiA). ClinicalTrials.gov. Updated August 23, 2024. Accessed December 11, 2025. https://clinicaltrials.gov/study/NCT02032823
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