We need to change the way we think about genetic variation

An extra from The uncertain future of genetic testing

Genetic variants that cause disease are rare, but this does not mean that all rare variants cause disease. Professor Nazneen Rahman, of the Institute of Cancer Research in London, says we should start managing uncertain variants as benign unless there is evidence to the contrary.

Uncertainty about the impact of genetic variants is a hot topic because so many more people are now having genetic testing. It is a complex area and a recurring theme in the Transforming Genetic Medicine Initiative, which is building the foundations needed to make genetic medicine work. But it is clear that if we want to improve the ways we manage uncertainty in genetic testing, we need a fundamental change in how we think about genetic variants. 

Resetting the baseline

The most important adjustment we all need to make is changing our baseline assumption about how likely a variant is to cause disease. It used to be assumed that a rare genetic variant found in someone with disease had a high chance of being involved in causing that disease. Variants were considered guilty until proven innocent. In part this was because for many years gene testing was only performed in people with disease. But once gene testing became cheap and easy we could look at the genes of many thousands of people, both with and without disease. The results have been surprising and transformative.

It turns out that rare genetic variants are the norm. We all have hundreds of them.

My colleagues and I studied all 20,000 genes in 1,000 random people from the UK general population. We found that, on average, each person had 22,000 variants, of which 160 were very rare, not present in anyone else in the study. Among these were, on average, six of the most severe types of variant, which stop the gene from working at all. This might seem surprising, but we each have two copies of every gene, so even if a genetic variant stops one copy working, the second copy can often cover for it.

Variants should be considered innocent unless proven guilty

Many other studies have shown exactly the same thing: although disease-causing (pathogenic) variants are rare, most rare variants do not cause disease – in the same way that most bananas are yellow but most yellow objects are not bananas. This means we need to reset our baseline. Instead of considering genetic variants guilty unless proven innocent, we should consider them innocent unless proven guilty.

This reset is so important because it profoundly influences the choices doctors and patients make. For example, so-called variants of uncertain significance (VUSs) in the BRCA genes are often managed in the same way as pathogenic variants, because they are assumed to be guilty in the absence of evidence that they are innocent. Entirely healthy women have surgery to remove their breasts and ovaries because they believe a VUS puts them at higher risk of developing cancer. In fact it is unlikely that such a variant is having an impact on their cancer risk. It is far, far more likely the variant is just a normal part of the rare genetic variation we all have. Women with a VUS should weigh their options in the same way as women with variants that are known to be innocent. 

Communication is key

There are many other examples of unnecessary and harmful interventions occurring because of this simple yet fundamental misunderstanding about the likely impact of rare genetic variants. To stop these harms happening we need to communicate effectively, to health professionals and patients, that genetic variants are a normal part of us and are mostly harmless.

If we can get this right it will greatly reduce the anxieties that genetic testing can induce and will allow us to focus our energies on identifying the small proportion of genetic variants that really do cause disease.


Professor Rahman and the Transforming Genetic Medicine Initiative are funded by Wellcome, the publisher of Mosaic.