Testing more than 4,000 BRCA1 gene changes in breast cells could help sort ‘uncertain’ genetic test results by cancer risk, London lab finds
Some changes that look harmful in a standard lab cell had little effect in breast cells, and those carried a middle level of risk. The method is not yet used in clinics.
A lab method that tests thousands of possible changes in the BRCA1 gene, in breast cells as well as a standard lab cell, could help doctors tell people more precisely how much a given change raises their breast cancer risk, researchers at the Francis Crick Institute in London reported Nov. 11 in the journal Nature Genetics.
BRCA1 normally helps repair damaged DNA, and harmful changes in it raise the risk of breast and ovarian cancer. Yet more than half of the single-letter BRCA1 variants reported so far lack a clear answer on whether they are harmful, the paper says. People who get such a result from a genetic test can be told only that its significance is unknown. “This leaves them in the dark about their risk of developing cancer,” said Greg Findlay, who leads the Crick’s Genome Function Laboratory.
What they found
- The team tested 4,113 BRCA1 variants that had not been tested this way before and found 538 that impair the gene.
- Scores from a standard lab cell line, called HAP1, separated known harmful variants from known harmless ones with near-perfect accuracy, the authors wrote.
- Nearly half of the variants that damaged the gene in HAP1 cells scored as normal in human breast cells. Those variants were tied to an intermediate cancer risk, the team found.
- Variants that were harmful in both kinds of cells were tied to higher breast cancer risk.
Findlay said that one day, people could get “a precise risk estimate” instead of a simple yes-or-no answer.
How it works
The method, called saturation genome editing, uses gene editing to put each possible variant into cells growing in a dish, one at a time, and measures whether each change affects how well the cells grow. The Crick team built a new version of the test in human mammary epithelial cells, breast cells more relevant to breast cancer, so results could be compared across cell types.
Limits
This is lab research. The risk links come from comparing the lab scores with existing data on cancer risk, not from following patients. The results are not yet part of routine genetic test reports, and the researchers describe better interpretation as a future possibility.
Sources: Francis Crick Institute news release, Nov. 11, 2026; Dace et al., “Saturation genome editing of BRCA1 across cell types improves interpretation of variant pathogenicity,” Nature Genetics, Nov. 11, 2026.