Cancer-related gene variations often reclassified, shows study

Almost a quarter of all cancer gene test variations were amended due to reclassification over the course of a decade, a new study has found.

The retrospective research looked at 1.67 million genetic tests from a single laboratory for hereditary cancer risk in 1.45 million patients at the University of Texas Southwestern Medical Centre from 2006 to 2016.

Overall, 24.9 percent of genetic variants previously classified as variants of 'unknown significance' were reclassified, with most (91.2 percent) being downgraded in risk to likely to be benign or benign. A few (8.7 percent) were upgraded to likely to be pathogenic or pathogenic. However, the reclassification of variants that were initially classified as benign or pathogenic was very rare. 

'Physicians need to be aware of how rapidly knowledge about gene variants is advancing and that reclassifications are common,' said Dr Theo Ross at Southwestern, based in Dallas, and lead author.

Genetic testing for hereditary conditions, including cancer, is becoming increasingly common as access becomes easier and cheaper. While sequencing of the genome is not the problem – interpretation is challenging, as the human genome is highly variable and earlier studies have found a median of over 20,000 gene variants per person.

This means that it often remains unknown whether a certain variant in a gene poses a risk for the patient. People who have a genetic test might therefore receive the information that their gene contains a variation from the norm, but they do not necessarily know if this will have a good, neutral or bad effect on their health.

'We are getting new data all the time. We may identify new families that have an inherited susceptibility to cancer and learn something from their DNA,' said Dr Ross. 'Labs may determine the atomic structure of the protein product of the gene with the variation and see an abnormal shape or find that cells with the variant gene don't behave as expected. With collective familial, biochemical, and functional data all pointing to abnormal, a variant is reclassified from "variant of uncertain significance" to "pathogenic".'

The researchers found that 59,955 amended reports that contained reclassified variants were issued between 2006 and 2016. Because most variants were observed in more than one person, 24.9 percent (46,890 of 184,327) of all variants of uncertain clinical significance were reclassified.

The team points out that issuing these reports has important implications for the patients, as they can either provide peace of mind or warn of possible health risk. 'If a variant is reclassified to being pathogenic, then it matters to the patient,' said Dr Ross. 'For example… if they have a broken BRCA gene, they may want to have prophylactic surgery or add MRI scans to their mammogram screening programme.'

The study, published in JAMA, highlights the importance of revisiting genetic testing results on a regular basis said the authors.