Learning you carry a BRCA genetic mutation, which you may know as the one that puts people at significant risk for breast and ovarian cancer, throws your world off its axis. In too many cases, your test results are handed to you in a folder from the diagnostic company Myriad Genetics, the company that wholly owns the rights to the test, with phrases like “75 percent lifetime risk of breast cancer” and “a c.783T>G (p.Tyr261*)-mutation,” without any explanation of what those things mean or what to do next. At the time I received mine — this was 2015 — Myriad would not allow any other labs to test for the mutation, so a second opinion was also out of the question.
My inability to understand these results was a result of being tested for the mutation by a gynecologist, whose area of expertise was not hereditary disease. I knew that having the mutation meant the probability of getting breast and ovarian cancer was much higher for me than the average American woman. In the days following the test, I learned I had two options: a series of scans and blood tests every six months, or risk-reducing surgeries to remove my breasts, ovaries, and fallopian tubes. I learned all of this information in the span of two weeks, and I made the decision to have a mastectomy at the age of 27 while surveilling my ovaries and fallopian tubes until I am 35, when it’s recommended I remove both. But these choices were made without any other information about BRCA mutations. I’ve since learned the correct next move for people with BRCA mutations is to get a genetic counselor, because there may actually be no need to do anything.
Since Angelina Jolie announced in 2013 that she carries a BRCA1 mutation and underwent two risk-reducing surgeries, removing her breasts, ovaries, and fallopian tubes, there has been an uptick in women making similar, but uninformed, decisions upon finding out their BRCA status. It was not until a recent study in Nature that I learned BRCA mutations are classified in three forms: pathogenic, which account for up to 10 percent of breast cancer diagnoses; benign; and variant of unknown significance (VUS). Within each of these categories are thousands of variants. In the days leading up to my mastectomy three years ago, I learned I might be in the 25 percent of women with a BRCA mutation who don’t get cancer. This latest study threw me back into that moment: Did I undergo this surgery for no reason?
The preferred method of BRCA testing is for patients to first consult with a genetic counselor, whose sole purpose is to educate patients on their hereditary risk of disease. After a BRCA test is given, the counselor then discusses the results and the patient’s options for surveillance and surgery. While these are generally the only two options, a counselor or doctor might suggest one over the other depending on the patient’s age and family history.
Everyone carries two BRCA genes: BRCA 1 and 2. The genes are tumor suppressors, and when mutated, they can increase a person’s risk of breast, ovarian, and pancreatic cancers. If I spoke with a genetic counselor today, they would confirm that my mutation was actually pathogenic and the surveillance and surgical options I was given by a breast surgeon and gynecologic-oncologist remain the best choices for someone in my position. Still, there is a sizeable portion of women who may carry certain mutations and get swept up in a course of drastic action where none may actually be necessary. A 2017 study revealed that one in 500 mutations with unknown significance were reclassified at pathogenic. But, in general, only 12-15 percent of tested BRCA 1 and 2 mutations are classified as pathogenic.
Genetic counseling has been available, though underused, since the Utah-based Myriad Genetics introduced the BRCA blood test 22 years ago. “There isn’t a lot of clinical data, or it’s in a silo held by Myriad,” Lea Starita, one of the authors of the Nature study, said in a statement. For over two decades, Myriad’s proprietary list of over 17,000 BRCA1 variants has been closely guarded, despite petitions, lawsuits, and a lot of angry patients who could not afford the company’s $3,000 test.
Women who test positive for a mutation variant of unknown significance often feel paralyzed, hoping science advances faster than the possible growth of cancer.
Women who test positive for a mutation variant of unknown significance often feel paralyzed, hoping science advances faster than the possible growth of cancer. As a result, women may undergo risk-reducing surgery as a precaution. Some physicians and genetic counselors believe this reaction to be hasty, and even irresponsible: per the Journal of Clinical Oncology, between a quarter and half of surgeons who deal with breast cancer patients treat the unknown-significance patients any differently from the pathogenic ones. Genetic counselors typically do not advise VUS carriers to undergo preventative surgery, as their variant may in fact cause no harm, which we’ve established as research of the gene expands. However, since the Myriad gene patent was invalidated in 2013 by the U.S. Supreme Court, mail-order companies like 23andMe promote a cheaper alternative to BRCA-testing with one caveat: there is no genetic counseling, and no guidance on what to do next. Given the prevalence of BRCA-testing and preventive surgeries in media, customers who test positive might feel pressure to take immediate action, like I did, without knowing whether surgery is necessary.
Knowing that they would never gain access to Myriad database of life-altering BRCA variants, Starita and Jay Shendure, another author of the study, and eight other scientists used CRISPR, a gene editing tool, to engineer nearly 4,000 BRCA variants. And, perhaps in defiance of Myriad’s imprisonment of this information, the results of the latest Nature study now live on a public database in which mutation carriers can search for their specific variant. Jay Shendure, another of the authors, said in a press release, notes “I might sequence the BRCA1 gene in a woman and observe that she has a mutation, but I don’t know whether that mutation will actually lead to an increased risk of breast cancer or whether it will be perfectly harmless.” Both physicians and patients are put in a position where the consequences are unknown.
A former clinical specialist at Myriad who wished to remain anonymous told The Outline it is rare for a VUS, the gray-area risk state, to be reclassified in the dire pathogenic category. But before they’re classified, the women carrying the mutation live in a terrifying limbo. With a pathogenic mutation like my own, there is a degree of certainty on which clinical decisions can be made. Before the CRISPR-generated database, physicians and genetic counselors could search ClinVar for the most common variants and variants known, unambiguously, to cause cancer. The National Institute of Health was forced to create this database using its own research, since Myriad Genetics refused to share their data, which would have given us a more robust source of information and the ability to cross-match classifications.
Dr. Susan Domchek, the director of the Basser Center for BRCA, told The Outline how Shendure and Starita’s study would affect how she counsels patients. “This is a valuable additional dataset to consult when dealing with genetic findings, but we will continue to use all sources of data which help classify variants,” she said. “Who is to say that this [study] is correct and ClinVar is wrong. This paper has provided an incredibly valuable functional analysis to consult…but should be viewed in conjunction with other pieces of evidence.”
In creating an open database for doctors and patients to search their mutation, and by classifying 2,000 more VUSs as either benign or pathogenic, this new study brings a sense of clarity to BRCA testing, and should not induce the same panic I felt when initially reading it. Still with every new study on BRCA mutations, experts like Domchek say there needs to be a stronger emphasis on counseling patients to figure out how this new information might affect them.
Update 9/24/2018 3:15pm: A prior version of this article asserted that genetic testing company color does not offer genetic counseling to customers. Color offers counseling to patients who purchase one of their genetic test kits. The counseling is available to the patient before and after taking the test, but only after the test is purchased. With in-person BRCA blood tests, when you go through a genetic counselor, counseling is provided prior to ordering any type of testing to determine which (if any) genetic test is most appropriate for the patient and confirm that the patient understands the implications of a positive test result. The counseling provided after testing is done regardless of a positive or negative test result. As of 2016, at least two insurance companies, including United Healthcare and Cigna, require genetic counseling prior to authorizing coverage for the test, to avoid the unnecessary cost for patients who may not fit the criteria.