Heterozygous variants in intermediate-to-low penetrance FANC-family genes with emerging evidence in breast cancer patients: experience of a cancer genetics reference center in Colombia

Breast cancer is a disease that touches millions of lives, yet for many families, the reason it strikes remains a mystery. While scientists have long known that changes in two specific genes, BRCA1 and BRCA2, can dramatically increase a woman's risk of developing the disease, these famous genes only explain a portion of hereditary cases. In the remaining families, the genetic cause often hides in plain sight, tucked away in a vast network of other genes that work together to repair damage to our DNA. One such network is known as the Fanconi anemia pathway. In its most severe form, when a person inherits broken copies of these genes from both parents, it causes a rare childhood disease called Fanconi anemia. However, when a person inherits just one broken copy from a parent, they do not develop the childhood illness. Instead, they carry a hidden vulnerability that might make them more susceptible to breast cancer later in life. Understanding how these single copies behave in different populations is crucial, because the genetic makeup of people in Latin America has been largely missing from the global map of cancer research.

In southwestern Colombia, a team of researchers at a high-complexity medical center set out to fill this gap. They looked back at the medical records of 663 women and one man who had been diagnosed with breast cancer and had undergone genetic testing between 2013 and 2025. Their goal was to see how many of these patients carried a single, altered copy of the genes in the Fanconi anemia family, excluding the well-known BRCA genes. They focused specifically on genes that are thought to carry a moderate or lower risk, rather than the very high risk associated with the major genes. By examining the DNA of this specific group, the researchers hoped to uncover patterns that could help doctors better understand who is at risk and why.

The study revealed that nearly one in ten patients in this group carried a variant in one of these intermediate-risk Fanconi genes. Specifically, 61 out of the 663 patients tested positive for such a change, representing a prevalence of 9.20 percent. This finding suggests that these genes play a more significant role in the region's breast cancer landscape than previously documented. The patients who carried these variants were mostly women, with a median age at diagnosis of 49 years. The tumors they developed were diverse, but a notable portion fell into a category known as triple-negative breast cancer, a type that is often more aggressive and harder to treat. Among the patients with this aggressive subtype, the researchers found a higher concentration of variants in specific genes, hinting that these genetic changes might be linked to this particular form of the disease.

When the scientists looked closely at the specific genes involved, three stood out as the most common sources of these variants: FANCM, FANCA, and FANCD2. Together, these three genes accounted for more than two-thirds of all the findings. The most frequent gene affected was FANCM, followed closely by FANCA and FANCD2. The researchers also noticed something intriguing about the specific changes found in the DNA. One particular alteration in the FANCM gene appeared in five unrelated patients from the same region. This repetition suggests that this specific genetic change might have originated from a common ancestor in the area, a phenomenon known as a founder effect. While this specific change has not yet been proven to cause cancer on its own, its repeated appearance in local patients makes it a strong candidate for further study.

A significant challenge in this work was the nature of the genetic changes themselves. In about two-thirds of the cases, the researchers identified variants that were classified as having uncertain significance. This means that while the change in the DNA is real, current scientific knowledge does not yet allow doctors to say for certain whether it causes cancer or is harmless. This uncertainty is common in regions where large databases of genetic information from local populations are missing. Without these local reference points, it is difficult to tell if a genetic change is a unique local trait or a rare error. The high number of these uncertain results highlights a pressing need for Latin American genomic databases, which would allow doctors to interpret these findings with greater confidence.

Despite the uncertainty surrounding many of the specific changes, the study provides a clear picture of the genetic architecture of breast cancer in this part of Colombia. The researchers found that the genes FANCM, FANCA, and FANCD2 are the primary players in this intermediate-risk category. They also observed that patients with triple-negative breast cancer were more likely to carry variants in FANCA, FANCM, and FANCC. This association is important because it suggests that these patients might benefit from specific treatments that target DNA repair mechanisms, such as certain chemotherapy drugs or newer targeted therapies. The study also noted that one male patient carried a variant, reminding medical professionals that men with breast cancer should not be overlooked in genetic screening programs.

The researchers were careful to note the limits of their work. Because the study looked back at existing records, it could not prove that these genetic changes directly caused the cancer, nor could it calculate the exact risk for any individual. The group of patients was also selected from a specialized clinic, meaning the results might not perfectly represent every person with breast cancer in the country. Furthermore, the genetic tests used over the years varied in their design, which could have influenced which changes were detected. However, the consistency of the findings across a large number of patients gives weight to the conclusion that these genes are relevant.

Ultimately, this study offers a new layer of understanding for doctors and families in southwestern Colombia. It confirms that when the well-known BRCA genes are not the cause, the Fanconi anemia pathway genes are a likely next step to investigate. The discovery of a potential regional founder effect and the link to aggressive tumor types provide a roadmap for future research. By building local genetic databases and continuing to study these intermediate-risk genes, scientists hope to move from uncertainty to clarity, ensuring that patients receive the most accurate risk assessments and the most effective care possible. The work underscores that while the genetic code is universal, the story it tells can vary significantly from one region to another, and understanding those local stories is essential for the future of cancer care.