NEW YORK (GenomeWeb) – Quest Diagnostics and the French National Institute of Health and Medical Research (Inserm) said today that researchers working within the BRCA Share project have been able to classify almost 400 variants that previously had unclear links to cancer to more definite categories.
In launching the public-private initiative last year, Quest and Inserm aimed to share clinical, epidemiological, and biological data on these two genes, which are associated with increased risk for breast, ovarian, and other cancers. They had specifically stated their intention to gather more evidence on variants of unknown significance.
Researchers, physicians and patients can access information in BRCA Share for free, though commercial labs have to pay an annual fee that is determined on a sliding scale to Inserm to support research and upkeep of the database. All users have to register for access to the data to BRCA1 and BRCA2.
Other than Quest and Inserm, participants in BRCA Share include Laboratory Corporation of America and the French Unicancer Genetic Group, which includes 16 academic labs that conduct BRCA1/2 testing in France.
Over the past year, Quest and LabCorp, two of the largest reference labs in the US, have added 1,300 new BRCA variants to the existing information that Inserm had within the Universal Mutation Database (UMD) project in France. Quest and LabCorp detected these variants over the three years they have been offering BRCA testing. Quest launched its BRCAvantage test in October 2013, and LabCorp launched Comprehensive BRCAssure in December of the same year.
In total, BRCA Share now contains 6,200 unique variants, marking a 30 percent increase from the information previously in UMD. Within this dataset, researchers have newly classified 334 variants as pathogenic or likely pathogenic, increasing by 20 percent the total number of clinically significant variants in this category, to 1,826.
Importantly, researchers were able to reclassify 93 percent of 375 variants that were previously variants of unknown significance as neutral or likely neutral in terms of cancer risk, and deemed 7 percent as pathogenic or likely pathogenic. Quest, Inserm, and other participants in the project are happy with this initial data, said Charles Strom, VP of genetics and genomics at Quest, who told GenomeWeb that the level of reclassification from VUS to actionable results had exceeded his expectations.
However, since its launch, LabCorp and Quest have beeen the only two commercial labs participating in BRCA Share. BRCA Share's model is one that depends on commercial lab participants to pay an annual fee to Inserm, based on a sliding scale, to fund research and administrative expenses.
At the time BRCA Share was launched, Quest spokesperson Wendy Bost told GenomeWeb that small labs would pay around $10,000 annually, while larger labs might have to commit in the hundreds of thousands of dollars. But, she noted, as more commercial labs joined the effort, the fees would decrease.
Skepticism and misunderstandings about the scope of the effort may have discouraged commercial labs from joining, Strom said. However, he hoped the latest data from BRCA Share will encourage more participation.
BRCA1 and BRCA2 are large, highly variable genes. Myriad Genetics was the only lab in the US testing for these genes for close to 20 years, but competition increased after the US Supreme Court in 2013 invalidated several of Myriad's patent claims related to its BRCAnalysis test. Myriad has amassed an internal database containing information on 17,000 BRCA variants, and as of 2013 claimed that 0.6 percent of BRCA1 and 1.6 percent of BRCA2 test results report variants of unknown significance (VUS).
When patients receive pathogenic results from BRCA testing, denoting a high risk for breast and ovarian cancer, they can decide to reduce their risk through surgical removal of the breasts and ovaries. But because patients cannot act on VUS results, these create uncertainty for them.
As competition in the US has increased and labs are testing for BRCA genes that previously didn't have much experience assessing them, researchers and industry players have banded together to start data sharing efforts to identify when labs are reporting the same variant differently, advance consensus classifications, and reclassify VUS to more definitive categories.
One such effort is ClinVar, an NIH-funded archival database of genotype and phenotype relationships that is public and freely available. Meanwhile, the National Human Genome Research Institute has also funded ClinGen, which aims to create a central resource for clinically relevant genes and variants that can be used for precision medicine.
More than 500 labs and researchers have submitted variant information to ClinVar to date, including Quest. Panels of experts convened by ClinGen review data in ClinVar and submit their interpretations back into the database. Specifically on BRCA genes, ClinVar contains information on more than 3,700 and 4,800 variants on BRCA1 and BRCA2, respectively.
Strom said that Quest is working on uploading its data to ClinVar. "It's not trivial. It's a bulk upload of tens of thousands of variants," he said, adding that the lab is interested in participating in ClinGen as well.
However, he noted that unlike ClinVar, BRCA Share is a curated database. He claimed that "anybody can upload anything" into ClinVar, and there is no effort within that project to ensure that entries aren't duplicated, to check for typographical errors, or to determine whether the classification is correct.
Heidi Rehm, one of the principal investigators of ClinGen, countered that experts working within ClinVar do ensure that each submission has the correct nomenclature, is mapped accurately to the reference genome, and that ClinVar doesn’t contain duplicate entries. While ClinVar allows multiple sites to submit their own interpretations, this is the whole point of the database, she said. "We don't all agree with each other and we need a way to 'share and compare' so we know where the differences are and can resolve them," she told GenomeWeb over email. "In fact, now that we have lots of data on ClinVar, the discrepancies are being resolved."
Also, a number of labs contributing substantially to ClinVar have told GenomeWeb that they are putting a lot of resources and manpower behind curating the data internally before submitting to the database. ClinVar provides a monthly discrepancy report that lays out classification disagreements between labs, which submitters use to review variant classification conflicts internally.
The system seems to be working, according to Rehm. She highlighted that when the international consortium ENIGMA submitted its expertly curated BRCA1/2 variants to the database, submitters from the Online Mendelian Inheritance in Man, a compendium of genes and phenotypes, "immediately went in and fixed several entries from the literature where the author's interpretations were clearly wrong."
In her perspective, ClinVar and BRCA Share are doing the same work and are not that different. "We'd obviously love to be able to compare BRCA Share data to the data in ClinVar, so we can identify differences and work to resolve them so we can all improve the care we provide to patients," Rehm said.
In announcing the release of the new data, the collaborators in BRCA Share claimed that theirs was the largest database providing access to researched and curated BRCA data. BRCA Share uses the curation process developed by Inserm, Institut Curie, and the Unicancer Genetic Group.
Furthermore, researchers monitor nomenclature errors and take out duplicate data that can give the impression that a variant occurs more frequently in the population than it actually does. Quest had also said that it would facilitate researchers' ability to perform functional assays to investigate the association of rare variants to cancer, a capability that many labs don't have.
BRCA Share "doesn't just have the classifications but all the reasoning behind it, published literature references, functional studies, in silico modeling, and family studies," Strom noted. Using this data, "clinicians and scientists can check the curators' work."
In order to participate in the effort, commercial labs must submit their BRCA variant classificaitons to Inserm's variant team and allow it to research and curate the data. After the variant is curated or classified differently than what a lab submits, Inserm notifies the BRCA Share members and uploads the data into the database. "We'll always have confidence that we're giving the latest classifications for our patients, which is one of the expected benefits of joining the database," Strom said.
However, he noted that labs submitting to BRCA Share are free to disagree with Inserm's classification, since ultimately, they are responsible for reporting test results to patients. So far, 1,000 scientists from 49 countries have registered to access the data in BRCA Share.
Ultimately, Quest decided to advance BRCA Share to develop a clinical grade database for BRCA variants, Strom noted. "[It] took us a year to figure out how to upload tens of thousands of variants, still allow accurate curation, while allowing access to the global and scientific community," he said.