Genetic Tests Can Identify Breast Cancer Risk. Why Is It So Hard to Interpret the Results?

Sadia Zapp knew she was at an elevated risk for breast cancer. As managing director for communications at the Breast Cancer Research Foundation, Zapp is privy to the parts of her family and personal history that predisposed her to breast cancer—she got her period young, gave birth after the age of 30, and had an aunt who died of the condition.

Armed with this knowledge, Zapp asked for a preventive breast screening at the age of 36, four years before most women start routine mammograms. Instead, her doctor recommended a genetic test to identify variants, or mutations, that are linked to an increased likelihood of developing breast cancer.

Zapp’s test came back negative, or at least, that’s what her doctor shared with her. It came as a surprise, then, when she discovered a stubborn lump in her chest six months later and confirmed her breast cancer diagnosis. At her oncologist’s urging, she requested the full results of the genetic test.

The word “negative” dominated the report. But underneath, in smaller print, it said two “variants of unknown significance” had been detected.

“The second I saw that I was like ‘what?’ I was just appalled,” Zapp told Verywell. “That variant, in combination with all of these other risk factors, should have raised an alarm bell and it didn’t.”

These so-called variants of uncertain significance (VUS) are small tweaks in genes that scientists suspect could play a role in increasing someone’s breast cancer risk. These variants number in the tens of thousands—the breast cancer susceptibility 1 gene (BRCA1 gene) alone carries more than 800 variants of uncertain significance.

Zapp said the test results could have been pivotal for the trajectory of her cancer journey. They showed she tested positive for a variant in BARD1, a gene that is associated with a moderate risk for breast cancer. If she had known about the variant, she said she would have better advocated for herself, and the outcome might have been different.

“We’re doing a disservice to patients if we do not factor in variants of unknown significance,” Zapp said.

Some of the large panel genetic tests given in hospitals detect VUS in as many as 40% of patients screened. While most of these variants are likely benign, they all have some potential to be pathogenic. Given this uncertainty, cancer care providers are divided on how to best use the tests and how far to go when making care decisions based on the results. 

Some providers will treat VUS like other breast cancer risks, despite the uncertainties. In a 2015 study of 666 breast cancer patients, half of those who tested positive for a VUS in BRCA1/2 chose to get a double mastectomy, and up to half of the surveyed surgeons reported managing patients with these VUS the same way as those with known cancer-causing variants.

Other providers say it’s hasty to recommend a life-altering preventive surgery based on variants for which scientists don’t have much data. For this reason, some providers choose to share positive results with disclaimers or avoid sharing them at all.

Can Genetic Tests Detect Breast Cancer Risks Accurately?

Humans have more than 20,000 genes. When just one amino acid in these genes is swapped out for another, that’s called a mutation, or variation.

Genetic variation is “extremely common in the human species,” Mark Robson, MD, medical oncologist and Chief of the Breast Cancer Medicine Center at Memorial Sloan Kettering Cancer Center. 

When studying genetic variants that may be linked to cancer, scientists rate them on a five-point scale, from "benign" to "pathogenic." Robson said that with more research, scientists might find that most VUS are likely noncancerous.

Due to the uncertainty about their role in breast cancer, VUS are not usually considered “actionable," according to the American College of Medical Genetics and Genomics. That means clinicians should not take preventive actions, like recommending a mastectomy, based solely on the detection of a VUS. 

Some clinical lab tests have the capacity to detect as many as 84 different variants implicated in breast and ovarian cancer. Sharing a positive test result may give just enough information to worry patients, but not enough for clinicians to feel confident taking drastic action, Robson said.

“I’m generally not in favor of panels that include a lot of stuff that is either of uncertain implication or is necessarily not associated with the condition that the person is coming for—a family history of breast cancer family history of ovarian cancer,” Robson said. “I don’t personally take it as an opportunity to do population screening for conditions that have nothing to do with what the patient was asking about.”

Robson said he falls on the conservative end of the spectrum of cancer geneticists. Although he’s not opposed to encouraging a patient with a VUS to receive more frequent screening, recommending a preventive surgery based on an uncertain risk factor could have severe consequences.

Increasingly, clinicians are using polygenic risk scores to make sense of an individual’s cancer risk before recommending a preventive measure as drastic as a mastectomy. These risk scores account for both the genetic and clinical risks of breast cancer to make better sense of someone’s overall likelihood of developing the disease.

Genetic Test Results Require Interpretation

By the time Zapp noticed the lump in her breast and received a diagnosis, her cancer had progressed to stage two. She’s now undergoing chemotherapy, then will get surgery followed by radiation. 

“If I had truly done my homework and read my full results, things could have been very different for me,” Zapp said.

Still, she said she wished her doctor had been more forthright about the VUS she carries. Per the 21st Century Cures Act, patients should have access to all of their health records. But when patients don’t explicitly ask for that report, they may miss out on the full information.

“Patients present their doctors with dots on the page, and we are relying on that doctor to connect those dots and see the picture. That failed in my case,” Zapp said. “On one hand, knowledge is power. But on the other hand, is it really, if you don’t have help to translate that information?”

For patients like Zapp, seeking advice from a genetic counselor or a clinical cancer genetics expert can help them make sense of complicated medical information in a meaningful way.

For those with a family history of the disease, a negative result on a genetic test doesn’t necessarily mean the patient carries no genetic risk for breast cancer. And a positive result doesn’t always mean a patient needs to take drastic preventive action.

“That’s where it’s really handy to be talking with a genetic counselor to put the results into that context,” Joy Larson Haidle, MS, CGC, a genetic counselor specializing in breast cancer genetics at North Memorial Cancer Health Center, told Verywell.

“While the gene test might be negative, if there’s a personal or family history, we might still be making suggestions of what surveillance could look like based on the family history and current guidelines,” she added.

As technology improves, new variants may become detectable, or scientists may learn that a variant previously considered to be of uncertain significance is actually pathogenic.

“It’s helpful to be able to continue a relationship with a genetic counselor or provider with experience with those genes to incorporate that data real-time into your medical care so that you don’t feel like you’re falling through the cracks or missing out on an important opportunity,” Haidle said.

Will Genetic Testing Become a Routine Part of Cancer Screening?

Thanks to advancements in genetics research and technology in the last decade, genetic testing has become much more accessible. Clinical lab tests are now less costly. And companies like 23andMe allow people to get a genetic test without stepping foot in a hospital. 

According to the CDC, people are recommended for clinical lab testing if they have a strong family history of breast cancer, a personal history of breast or some other cancers, or a known genetic risk of BRCA1 and BRCA2 mutations.

But there is no routine testing for these actionable variants and research indicates that about half of people with disease-causing variants in these genes don’t get medical attention.

“We are missing a lot of people who don’t necessarily come to medical attention because they don’t have the family history. Maybe they don’t know their family history, or it just hasn’t manifested in that way for them,” Noura Abul-Husn, MD, PhD, an associate professor of medicine and genetics at the Mount Sinai Icahn School of Medicine and Vice President of Genomic Health at 23andMe, told Verywell. “With that knowledge, you're able to make management decisions to reduce the risk.”

The 23andMe test is approved by the FDA to detect three key cancer-causing mutations in the BRCA1 and BRCA2 genes. However, unlike the larger laboratory panel tests, it doesn’t capture any of the VUS. While at-home testing may catch BRCA mutations in people who were unaware of their family history of breast cancer, Haidle said, the results should be corroborated with a lab test and those receiving any sort of testing should seek guidance in understanding the results. 

Robson said it’s possible that it could soon become standard of care to offer testing for variants that are known to be disease-causing. Variants in BRCA1 and BRCA2 are so actionable, he said, that testing for those could be offered to all older adults or other high-risk groups.

But running full panel tests for dozens of genes is “running too far ahead of our knowledge base,” he said.

As technology improves and research accelerates, scientists will gain a better handle of which variants are pathogenic and which are benign. Eventually, Robson said, there may be enough research for experts to reach a consensus on the best course of action for certain VUS.

“Variants of uncertain significance will always be with us because I don’t think anything’s ever really perfect and there’s a lot of variation among humans. But I do think that we’ll be able to reduce the number of them that are truly uncertain with time,” Robson said.