Image credit: GA4GH
October 18, 2023
By Rose Miyatsu
A project to expedite the analysis of variants on the BRCA 1 and 2 genes, the most commonly affected genes in breast cancer cases, will help more people to better understand their cancer risk.
While women on average face a 1 in 8 chance of developing breast cancer in their lifetime, this risk rises to roughly 2 in 3 for women who inherit a harmful variant in one of the BRCA genes. Genetic testing for variations of the BRCA genes has become more common, particularly for people with a history of breast cancer in their family. Knowing if they have a specific variant that increases cancer risk can help patients take actions to mitigate those risks, such as increasing the frequency of their cancer screenings, or in some cases even undergoing a preventative surgery.
There are tens of thousands of BRCA variations, however, and while some significantly increase a person’s cancer risk, others are benign and do not impact cancer risk at all. ClinVar, a public archive of genetic variants, has labeled almost 5,000 of 31,340 known BRCA variants as being of “unknown clinical significance,” and another 7,600 variants have received conflicting interpretations, leaving it unclear whether they are harmful or not. Scientists estimate that probably only about 15% of variations increase cancer risk, but sorting out which are likely harmful and which are likely benign is slow work.
The uncertainty surrounding variations of unknown clinical significance can be unsettling to the people who find out that they have them. Melissa Cline, a researcher for the UC Santa Cruz Genomics Institute and program manager for the BRCA Exchange platform that pools data on BRCA 1 and 2 genetic variants, is working on a project to expedite variant review. In the very near future, these efforts could provide clear answers about risk for thousands of these variants.
“I get emails from women who are worried because they have found out that they have a variant of unknown significance and they are worried and want to know what I can tell them about their variant,” Cline said. “We are working on a project now that will help us expedite the analysis of many of these variants so that very soon we expect to be able to provide better answers for the patients who carry them and their physicians.”
The BRCA Exchange works closely with ClinGen, an NIH-funded resource dedicated to defining the clinical relevance of genes. To assess the clinical relevance of genetic variants, ClinGen has teamed up with the American College of Medical Genetics (ACMG) and the Association for Molecular Pathology (AMP) to come up with guidelines to standardize how variations get interpreted and labeled as “Benign” or “Likely Benign” (those that show no evidence of increasing cancer risk), or “Likely Pathogenic” or “Pathogenic” (associated with an increased risk of cancer). These general guidelines are refined by the ClinGen Variant Curation Expert Panels (VCEPs), expert groups that adapt the guidelines to the genes under their purview. At BRCA Exchange, the researchers are beginning to expedite the work of these panels through automation.
“The rules for variant assessment are so detailed that it is difficult for researchers to apply them manually, but these detailed rules lend themselves very well to computational analyses,” Cline said.
The BRCA Variant Curation Expert Panel is identifying variants of unknown significance that they can curate easily based on computational evidence to harvest low-hanging fruit. Cline is streamlining evidence from population-wide studies so that they can find variants that are prevalent enough in given populations that they can safely be assumed to be benign.
The project will also use computational models to analyze evidence from high-throughput trials that experimentally introduce a variant into a cell line to see if it affects the functionality of the protein. This will help them to predict experimentally whether a variant will lead to a loss of function and is therefore likely pathogenic, allowing them to classify even variants that are too rare to have gathered much clinical data.
“I would say there are 2,500 variants conservatively that we hope to be able to curate right off the bat based on these assessments,” Cline said. “For women who carry these variants, that means not carrying the uncertainty.”
After the automated assessments are conducted, the variants will still need a final review from human curators, but it is Cline’s hope that the work she is doing will make it easy for these curators to quickly see which variants they can rule out and which ones they need to be concerned about. After the final review, the curated variants will get a badge of recognition from the FDA, which should give further confidence to clinicians as they make recommendations for patients with these variants.
The work BRCA Exchange is doing is possible because they have pooled so much data on the BRCA variants, and their database is becoming even more robust as other groups have decided to share their data. Cline has been particularly encouraged to see more open sharing from Myriad Genetics, a screening company that famously held a patent on the BRCA genes until the practice of gene patenting was struck down by the U.S. Supreme Court. Myriad has long held on to their own closed database of variants, yet recently began sharing some of its variant data with ClinVar, including 65 variants that were not previously in BRCA Exchange’s databases.
“I think the data-sharing climate we’ve created at BRCA Exchange is encouraging more players to come to the table,” said Cline. “At the end of the day, that will be a huge benefit for patients.”
The work described in this article is funded in part by grants from the Basser Foundation and the National Cancer Institute.