A major international study has revealed that only specific mutations in the FANCM gene are linked to an increased risk of aggressive forms of breast cancer, particularly estrogen receptor–negative (ER-negative) and triple-negative breast cancer (TNBC). One of the study’s authors is Nepali, adding national significance to this global research breakthrough.

The research, based on a meta-analysis of data from more than 268,000 women, combined large-scale genetic evidence with functional experiments to understand how different FANCM protein-truncating variants (PTVs) influence cancer susceptibility.

According to the findings, only mutations occurring in the N-terminal region of the FANCM protein significantly raise the risk of ER-negative and triple-negative breast cancer. Among them, the p.Arg658* variant showed the strongest association, doubling the risk of ER-negative breast cancer and increasing the likelihood of TNBC more than threefold.

In contrast, two widely observed mutations in the C-terminal region—p.Gln1701* and p.Gly1906Alafs*12—were found to have no meaningful impact on breast cancer risk, suggesting that these parts of the gene are less essential for cancer development.

Functional CRISPR experiments supported these results, showing that the N-terminal portion of the FANCM protein is critical for cell survival, while alterations in the C-terminal region have minimal biological impact.

Researchers say these findings will support more accurate genetic counseling, helping clinicians distinguish between high-risk and low-risk FANCM mutations when advising patients. They also highlight the need for continued research to refine risk estimates and better inform clinical decisions, particularly for women with family histories of ER-negative or triple-negative breast cancer.