In an oncogenetics consultation, one word can carry a lot of weight: BRCA1. When a result indicates a variant of this gene, the question quickly arises: what is the real risk for breast or ovarian cancer? The answer is not always clear-cut.
Work presented on November 11, 2026 by the Francis Crick Institute and published in Nature Genetics provide an important nuance: not all BRCA1 variants seem to have the same effect depending on the type of cell studied. But for those affected, this does not immediately change surveillance or prevention decisions.
Why can a BRCA1 result remain difficult to understand?
BRCA1 is one of the best-known genes in hereditary forms of breast and ovarian cancer. It intervenes in particular in the DNA repair. When certain variants strongly alter this function, they can be classified as pathogenic or probably pathogenic, with specialized treatment.
But not all results fall into such a neat box. Some people learn that they carry a variant of uncertain significance: the alteration is identified, but its clinical impact is not sufficiently established. This is one of the most uncomfortable situations in genetic testing for hereditary breast cancer, because it does not, on its own, predict individual risk.
The Francis Crick Institute team wanted to better explore this gray area. The researchers used a method called
saturation genome editingwhich involves introducing variants into cultured cells in order to observe their effect on gene function. It is a laboratory approach, useful for classifying variants. It is therefore not a question not from a cohort of patients followed over time, but from a laboratory risk assessment.
What does testing BRCA1 in breast cells change?
In a first cellular model, HAP1 cells, the authors report having tested 4,740 BRCA1 variants. They identified 538 variants with a functional impact. These effects could concern the interactions of the BRCA1 protein with other proteins involved in DNA repair, but also the expression of the gene or the production of the protein.
The most interesting step came next. The researchers compared these results with those obtained in human mammary epithelial cells, a model closer to the tissue affected by breast cancer. In this second model, 2,157 variants were scored. Result: certain variants which appeared deleterious in HAP1 cells had a much more limited effect in breast cells.
This difference suggests that biological context matters a lot. In other words, a variant can strongly disrupt BRCA1 in a type of laboratory cell, without causing exactly the same level of damage in breast cells. The authors suggest that certain cells could partially compensate for a loss of BRCA1 function.
“This suggests that breast cells can alleviate certain gene dysfunctions BRCA1″explains Phoebe Dace, co-author of the study. “Mutations selectively affecting HAP1 cells therefore appear to be associated with an intermediate risk of cancer. Identifying such mutations has not been easy until now, because their effects are less marked than those of mutations that affect the function of several cell types.”.
Conversely, the team demonstrated that harmful variants in both cell types are associated with an increased risk of breast cancer. This is explained by their greater impact on BRCA1’s ability to repair DNA.
This is where the main contribution of the study lies: the unfavorable variants in the two models seem more worrying than those which appear altered in HAP1 but neutral or less marked in mammary cells. The latter could correspond to a lower risk than the loss-of-function variants observed in both contexts.
What should a data subject in France remember?
For the moment, this work should not be read as a new individual instruction manual. A BRCA1 result cannot be reinterpreted alone, and even less so from a scientific article. In France, decisions regarding surveillance, imaging, prevention or risk reduction surgery are made by a specialized consultation, taking into account personal and family history and recognized classifications.
This point is essential to avoid an anxiety-provoking shortcut: a variant of uncertain significance is not equivalent to a pathogenic variant. It should not, on its own, lead to serious decisions. Conversely, a person with a suggestive family history may need an oncogenetic opinion even before any definitive genetic conclusion. Hereditary cancers and BRCA mutations are always interpreted in a family context.
The interest of the study is therefore mainly prospective: it shows that a more detailed reading of BRCA1 variants is possible, provided they are tested in relevant biological models. In the future, these types of results could help teams better distinguish high-risk variants from those with a more moderate effect.
“Ideally, people could be provided with an accurate estimate of risk, which would not only give them a clearer idea of their actual risk, but also help doctors decide what follow-up or interventions would be most appropriate to offer.“, says Greg Findlay, director of the Genomic Function Laboratory at the Crick
But before being translated into clinical recommendations, these data must be confirmed in the context of cohort monitoring.
Behind these results, an important perspective for those concerned: no longer consider all BRCA1 anomalies in the same way, but better understand their real impact. However, it will still take time before this approach can guide medical decisions. In the meantime, a genetic result must always be interpreted with an oncogenetics team, in light of personal and family history. Because better assessing a risk also means avoiding imposing overly burdensome decisions on those who may not need them.