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A study including data from more than 70,000 individuals shows that the chance of genetic variants labelled ‘pathogenic’ actually causing disease is low, although there is considerable variation between individual variants.

Many people now undergo tests to look for genetic mutations that may increase a person’s risk for disease such as those in BRCA1 and BRCA2 that are known to predispose women to breast and other reproductive system cancers. However, it can be hard to give an accurate prediction of how likely you are to develop disease if you carry such a variant.

To try and combat this problem, Ron Do, a researcher and associate professor at the Charles Bronfman Institute for Personalized Medicine at Icahn Mount Sinai, and colleagues carried out a study including 72,434 study participants—43,395 from the UK Biobank and 29,039 from the BioMe Biobank at Mount Sinai. The results of the study are published in the journal JAMA.

The participants were aged 20 years or older, had diverse ethnicities and were recruited between 2006 and 2010, with follow-up data until 2020. Overall, 5360 pathogenic or ‘loss of function’ genetic variants linked to 157 diseases were recorded in the cohort.

By looking at how many of the participants with potentially pathogenic variants had actually developed disease by 2020, the researchers found that only 7% showed signs of disease linked to carriage of a pathogenic variant.

“At first I was quite surprised by the results. The risks we discovered were lower than I expected,” said Do, in a press statement. “These results raise questions about how we should be classifying the risks of these variants.”

Despite the low overall risk for developing disease associated with most genetic variants considered to be ‘pathogenic’, the team notes that some had much higher penetrance than others. For example, carriers of the well-known BRCA1/2 variants had an average risk for going on to develop cancer of 38% and those carrying PALB2 variants, also linked to increased cancer risk, a 26% risk.

As there are a number of genetic mutations that can increase the risk for diseases in later life, it might be expected that older adults in the cohort carrying such variants would be more likely to have developed disease and indeed this was the case with an overall average penetrance value for late onset diseases of 10.3% in those aged 70 years or older versus 8.5% in those aged 20 years or older.

“While more research is needed to be done, we feel that this study is a good first step towards eventually providing doctors and patients with the accurate and nuanced information they need to make more precise diagnoses,” commented Do.

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