Mayo research sorts if rare BRCA2 mutations increase breast cancer risk

A Mayo Clinic-led team of researchers is solving one of the most frustrating aspects of genetic cancer screening — results that give zero guidance to patients on whether they are at elevated risk.

While some mutations in the BRCA2 gene clearly indicate risks for breast and prostate cancer, thousands of less-common variations have confounded doctors and left anxious patients without guidance when tests show that they carry them.

Mayo used gene-editing technology to analyze these “variants of uncertain significance” in one region of this key gene and reported last week that only about 250 of them were pathogenic, meaning they presented an elevated cancer risk.

Another 3,500 were benign, meaning that most of the mutations examined in this region of the BRCA2 gene don’t present an increased cancer risk.

The goal now is to communicate these updated findings to genetic testing labs, which can apply them when patients’ tests turn up positive for these variants, and provide clarity instead of confusion, said Fergus Couch, a lead author of the study and chairman of Mayo’s Division of Experimental Pathology and Laboratory Medicine.

“For the patients, it’s a real problem” when their tests find these variants, he said, “because they’ve paid their money, they got their test done and they actually got a result back. They found something, but then nobody has a clue what it does. So it’s very disconcerting for the patients. It actually causes a huge amount of stress ... because they can’t help thinking, ‘Well, maybe it actually does increase my risk of cancer.’ They don’t know what to do with it.”

The latest results were published in Nature, a prestigious scientific journal, and built on Mayo’s discovery in 2021 that it was possible to use gene-editing technology to test thousands of variations at one time to see if they were pathogenic. Previously, researchers examined mutations one at a time and had only determined whether a couple hundred were potentially harmful.

Genes are basically the code, passed down from parents to children, for human growth and development. Variations in the expression of these genes can causes differences in everything from eye color to blood type to cancer and disease risks.

Testing has increased tenfold over the past decade for mutations in the BRCA2 gene, which along with BRCA1 is considered a significant predictor of inherited breast cancer risks.

Mutations in these genes also have been predictive of ovarian, prostate and pancreatic cancers, allowing doctors to customize prevention plans for their patients. Options for patients at elevated genetic risk for breast cancer include more frequent breast exams, lifestyle changes, medications and surgical mastectomies.

“There’s lots of benefits to knowing if you have a real mutation or not,” Couch said.

Mayo’s latest findings don’t impact the mutations already known to increase cancer risks, but rather add new ones to the list of those considered pathogenic.

About one in 200 or 300 people carry the already-known variants in the BRCA2 gene linked to hereditary risks of breast cancer. Couch said these newly reclassified variants are less common, being found in about one in 1,000 people. Still, “that adds up to a lot of people” who can now receive clearer guidance, Couch said.

The researchers used gene editing to introduce the variants in question into cells, then determined if the variants were pathogenic based on whether the modified cells survived. The roughly $1 million project was funded by federal grants and the Breast Cancer Research Foundation in New York.

How quickly this information will filter to genetic testing sites and be used in interpreting patients’ results is unclear. Many centers conduct updates once every six or 12 months of genetic variants and how they are classified. Couch sits on a federal expert panel that reviews reclassifications of genetic variants, and said its approval of this work could hasten its usage.

Another challenge is notifying patients who have completed genetic testing, but whose cancer risks may now be better understood based on new knowledge of genetic variants they carry.

Researchers at the University of Texas Southwestern Medical Center in Dallas found earlier this year that these changes can substantially impact cancer prevention strategies for patients, but there is disagreement about who should communicate this updated genetic information to patients.

“When the information is delivered correctly, patients respond surprisingly well,” said Sukh Makhnoon, a public health geneticist at UT Southwestern. “The fact that most reclassifications are downgraded, meaning (their genetic variant) has no impact on cancer risk, helps too.”