Genetic testing is used to determine whether an individual carries a BRCA1 mutation known to increase their risk of developing cancer. This information can then be used to inform clinicians, allowing them to recommend if more frequent cancer screening is advisable or if preventative treatment should be considered. However, identification of unknown BRCA1 variants can leave patients and clinicians without the necessary information to make these decisions.
Dr Sean Tavtigian, who led the research team at the University of Utah's Huntsman Cancer Institute, explained 'there are tens of thousands of patients with unclassified variants in BRCA1'. Many BRCA1 mutations alter just a single amino acid without impacting the protein function. However, missense mutations can disrupt BRCA1 function, which in some cases will increase the likelihood of cancer development.
The research team focused on a section of the BRCA1 gene called the RING domain. This section helps the interaction of BRCA1 with its binding partner, BARD1. The interaction between BRCA1 and BARD1 is essential for normal BRCA1 functioning. Within the RING domain, there are nearly 600 possible missense mutations which could arise. The team created BRCA1 variants with each of these mutations to test how this would influence the binding to BARD1.
Published in the American Journal of Human Genetics, the team used a previously developed mathematical, point-based system to indicate the likelihood that each mutation could increase the risk of cancer. Of the mutations tested, 89 percent were classified as being benign, likely benign, pathogenic or likely pathogenic. Importantly, only 15-20 percent of these mutations were characterised as being pathogenic.
The laboratory findings were validated using medical data gathered from hundreds of thousands of people with and without cancer. These evaluations confirmed that the testing protocol devised by the team was a reliable indicator of a mutation increasing the risk of cancer development.
Dr Tavtigian suggested that researchers adopt this quantitative method of assessing the pathogenicity of genetic variants rather than using the more common approach of classifying mutations into discrete categories. The new model used during this research can be applied to any gene and does not require complex computer software.
'We are reaching the point where we should be able to classify all possible missense substitutions in BRCA1 over the course of the next few years' claimed Dr Tavtigian. Moving forward, the information gathered during this study could help to revolutionise the way that clinicians can evaluate their patient's risk of developing cancer.