Bringing genetics into medicine will lead to more accuracy, better diagnosis, and personalised treatment—but not for all. For Mosaic, Carrie Arnold meets families for whom gene testing has led only to unanswered questions. This article was first published by Wellcome on Mosaic , and it's republished here under a Creative Commons licence.

AnneMarie Ciccarella, a fast-talking 57-year-old brunette with a more than a hint of a New York accent, thought she knew a lot about breast cancer. Her mother was diagnosed with the disease in 1987, and several other female relatives also developed it. When doctors found a suspicious lump in one of her breasts that turned out to be cancer, she immediately sought out testing to look for mutations in the two BRCA genes, which between them account for around 20 per cent of families with a strong history of breast cancer.

Ciccarella assumed her results would be positive. They weren’t. Instead, they identified only what’s known as a variant of unknown or uncertain significance (VUS)—or two of them, one in both BRCA1 and BRCA2. Unlike pathogenic mutations that are known to cause disease or benign ones that don’t, these genetic variations just aren’t understood enough to know if they cause problems or not.

“I thought you could have a mutated gene or not, and with all the cancer in my family, I believed I would carry a mutation. I didn’t know there was this huge third category,” she says. “I got no information – it felt like a huge waste of blood to get a giant question mark.”

Thousands of people have had their BRCA genes tested for increased genetic susceptibility to breast, ovarian, prostate and other cancers. About five per cent have learned that they carry a VUS. That number can be even higher for other genes: in one study, almost 20 per cent of genetic tests returned a VUS result.

“That’s a lot of uncertainty,” says Robert Klitzman, a bioethicist at Columbia University in New York. People want genetic tests to be like pregnancy tests, he explains: “You’re either pregnant or you’re not. Instead, they’re more like a weather report.” And most people aren’t prepared to cope with the probabilities and uncertainties that entails.

When scientists surveyed a group of women one year after they received BRCA gene test results, the women whose results were uncertain or uninformative were feeling much more stress and anxiety than those whose results were clearly either pathogenic or benign. A follow-up study showed that the higher the risk an individual thought her result indicated, and the less tolerant she was of uncertainty, the more likely she was to experience serious long-term distress.

Even before her sequencing results came in, Ciccarella had decided on a bilateral mastectomy based on her family history. For her, the question of whether she would one day develop breast cancer had been answered, and in the worst possible way. But she still wanted information for her son and daughter so they could know whether they had inherited a genetic risk of cancer. Like a number of families, they are learning that genetic sequencing won’t deliver answers for everyone.

The variations in our genes

We are all mutants. The three billion pieces of DNA that make us who we are were long thought to be constant, chiselled in granite like a classical monument, with only tiny changes made here and there. Scientists used to believe that DNA mutations were largely harmful.

By the late 1990s and early 2000s, as the first sequences of the human genome came rolling in, researchers realised that their view of mutations was completely backwards. Instead of being rarities that almost inevitably harm health, mutations litter the human genome. The average human carries around 400 unique mutations, and most of us are none the worse because of them.

This challenged some basic tenets of genetics, as well as they ways that scientists and physicians interpreted genetic tests.

When Robert Resta, a genetic counsellor at the Swedish Medical Center in Seattle, first began examining genetic test results in the late 1980s, he could identify only chromosomal abnormalities or alterations of massive amounts of DNA. When other types of genetic tests were introduced, such as those for detecting the mutations in the CFTR gene that cause cystic fibrosis, interpretation was still reasonably straightforward. Because most of the people who had their CFTR gene sequenced showed clinical signs of cystic fibrosis, Resta could be reasonably confident that an observed mutation in that gene was the one that had led to the disease. In the past few years, however, the price of genetic sequencing has fallen dramatically, and doctors are increasingly requesting DNA testing earlier in the diagnostic process. As more data is gathered, the sheer number of mutations we all carry becomes more significant.

“It turns out mutations are the norm. You expect to find mutations in a gene. It’s a very different way of thinking about the human genome. If you don’t find a mutation, your machine is probably having technical difficulty,” Resta says.

When scientists test for mutations in large numbers of genes with a single test, known as a gene panel, they are virtually guaranteed to find at least one VUS, says Colleen Caleshu, a genetic counsellor at Stanford University’s Center for Inherited Cardiovascular Disease. “The more genes you look at, the more variation you’ll find,” she adds. “We all have tons of variations in our genes, most of which are extremely rare and, by the very nature of rarity, uninterpretable.” In short, there isn’t enough data to know what you are seeing.

This grey area has only expanded as next-generation DNA sequencing has led to the growing use of gene panels, to look for mutations in a range of genes that may be related to a patient’s symptoms. Of the three possible results – pathogenic, benign, or unknown – pathogenic is the least common, says Resta. You’re much more likely to get uncertainty.

If interpreting genetic testing results is difficult for clinicians, it’s also tremendously hard for patients. Yvonne Bombard has spent the last several years of her career as a genomics health services researcher at St Michael’s Hospital in Toronto, working to understand how families make sense of genetic testing results.

“There’s very little research on the impact of uncertain results on families yet – the technology is just too new,” Bombard says.

A small study in Psycho-Oncology surveyed 24 women with breast or ovarian cancer who had received VUS results for their genetic testing. Many of them had a distorted perception of what those results meant. Although two-thirds correctly remembered three years later that the variants detected by the test were unclassified, 79 per cent interpreted the results as a higher genetic risk for developing cancer. One-third had also made significant medical changes in their lives based only on their test results, which Resta and Caleshu do not recommend.

Families of children with suspected genetic diseases have similar difficulties. Parents tend to interpret any variant that’s not classified ‘benign’ as being the cause of their child’s disease, explains Caleshu. But she appreciates how it’s hard not to do that, especially when families have been looking for answers for so long.

Families can feel let down by the medical establishment, who often seem to throw up their hands when a patient defies diagnosis, and in the absence of definitive answers it’s all too easy to believe that the genetic variants identified on the test must be what’s wrong. One of Caleshu’s main jobs is providing pre-test counselling so that patients understand the risks and the limitations of testing. She says her team have changed the way they present results, so that patients and doctors don’t read too much into a VUS. Even with the right genetic counselling, however, uncertainty can be agonising.