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With BRCA Share, Quest Hopes to Provide Field With Variant Database to Support Clinical Decisions

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NEW YORK (GenomeWeb) – With careful curation and functional genomics analysis, Quest Diagnostics is hoping to speed up the classification of rarely seen BRCA mutations in cancer and set its BRCA Share initiative apart from other collaborative variant classification efforts.

Recently launched BRCA Share is jointly led by Quest, one of the largest reference labs in the world, and Inserm, France's national institute of health and medical research. So far, Laboratory Corporation of America, another large reference lab that usually competes with Quest, has signed up to submit data on BRCA mutations. But Quest is expecting participation to grow quickly, as it has received a number of queries from other interested parties.

In launching BRCA Share, Quest doesn't want to discourage labs and healthcare providers from submitting data to other public variant databases under development, such as the NIH's ClinGen effort. At the same time, Quest's Charles Strom is quick to point out that most currently available public resources aren't robust enough for labs to use when figuring out whether to report to a patient that a detected variant is benign, deleterious, or of uncertain significance. Quest is hoping BRCA Share will come to fill this need.

To participate in BRCAShare, labs must agree to submit all past, present, and future deidentified BRCA test results into Inserm's Universal Mutation Database (UMD), which has been collecting variant data for more than a decade from 16 French academic labs comprising the Unicancer Genetic Group. UMD will experience a deluge of data submissions, forecasted Strom, senior medical director of genetics at Quest Diagnostics Nichols Institute. Inserm currently has three dozen people working on curation and annotation, but Strom expects the institute will have to hire more experts.

"The costs are not trivial," Strom told GenomeWeb. While Quest is shouldering the finances initially for BRCAShare, commercial labs, such as LabCorp, that join the project must pay on a sliding scale in line with their size. Quest didn't disclose its own financial commitment to the project, but company spokesperson Wendy Bost estimated that small labs would pay around $10,000 annually while larger labs would have to commit in the hundreds of thousands of dollars. Quest expects that as more commercial lab join, the fees will decline.

What sets UMD apart from other publicly accessible DNA databases is its organization and curation, according to Strom.

The French group employs its own algorithm for calculating whether a variant is significantly associated with breast or ovarian cancer, and researchers physically monitor the database to fix nomenclature errors and take out duplicative data. Duplication errors are a particularly vexing problem in public databases, noted Strom, which can occur when multiple entries on a variant from an individual patient is submitted by his or her doctor, lab, and family members. If not fixed, this may give the impression that a marker occurs more frequently in the population than it actually does.

Importantly, Quest plans to facilitate researchers' ability to perform functional studies to uncover rare variants' association to disease. "If we find a variant we've seen a sufficient number of times in a user group, we'll use the clout of having this user group to find an in vitro assay that may be informative for this particular variant," Strom said. "This would be well beyond the capabilities of a normal clinical laboratory. We don't have enough researchers on hand to make an assay for every possible variant in BRCA1 or BRCA2."

BRCA Share comes as genetic data-sharing projects are undergoing a renaissance. Over the last decade, cash-strapped, open access variant databases have become infamous for being poorly maintained and littered with errors. Citing these very reasons, many labs have stopped submitting data to resources such as the Breast Cancer Information Core (BIC).

Then, in 2013, the Supreme Court invalidated a number of patent claims underlying Myriad Genetics' BRACAnalysis breast and ovarian cancer risk test, ending the company's nearly two decades-long monopoly over the BRCA testing market. As labs rushed to launch BRCA testing services, they tried to outdo each other on price and turnaround time for test results. However, in order to compete in terms of test accuracy with Myriad, still the market leader, labs had to lower the number of test results that identified variants with unknown or unclear links to cancer, so-called variants of unknown significance (VUS).

The fastest way to catch up to the level of data in Myriad's proprietary database, which contains more than 1 million tests results, would be for labs to pool knowledge on BRCA variants. In the US, the NIH's genetic data-sharing and interpretation effort, ClinGen, is allowing labs to do just that and so far has amassed information on 77,000 unique variants. With regard to BRCA mutations specifically, as of last summer ClinGen had 5,000 submissions. Additionally, a number of large cancer centers and commercial labs (including Quest and Myriad) banded together last year to try to learn more about VUS cropping up with increasing frequency due to greater use of next-generation sequencing panel tests.

Deleterious BRCA mutations increase a woman's risk for hereditary breast and ovarian cancer, and based on such a result a woman can decide to have risk-reducing surgery. But a VUS finding can create much uncertainty for a woman. Having tested more than 1 million women, Myriad boasts that around 2 percent of its results are for a VUS. By Myriad's estimates, other labs' VUS rates are as high as 30 percent — but these labs have countered that their rates are actually in the low-single digits.

I liken this to the [Human] Genome Project, where you had the public effort [which] was extraordinarily expensive and it took a lot of effort. Then you had Celera that came in with a very focused private effort and was actually able to achieve pretty much the same goal. Then, eventually, they merged.

Inserm's UMD currently contains data on around 16,000 BRCA1/2 variants. According to its website, around 1,400 out of 7,200 BRCA1 mutations and 2,800 out of 8,800 BRCA2 mutations are flagged as uncertain variants.

In Strom's view, VUS rates aren't necessarily the best way to measure the quality of a database, and emphasized that the level of curation and annotation as being far more critical. Bost further stated that ultimately it’s the lab's responsibility to determine a VUS classification, regardless of the classification in any database. "While lab members of BRCA Share will have discretion to make a VUS call on their lab reports, all members will receive the same information about the variant based on the UMD curation and annotation," she said.

Moreover, Strom argues that too much has been made of the size of variant databases. "It's really about service to the patient," he said. "They don't care if your database is a zillion variants … They care about whether they get returned a result that's of uncertain significance." This is where Quest hopes to distinguish BRCA Share, by conducting functional analysis to pinpoint the genotype-phenotype link for rare markers.

To illustrate his point, he gave the example of a lab that had performed 200,000 BRCA tests, and on the 200,001st test the lab identifies a VUS. It will take another 200,000 tests before the lab can hope to see that variant again. "So, even if you do a million tests, you've still only seen it five times. And that's not enough in and of itself to make a classification," he said. "Once you get up to a certain number of tests and a certain number of variants, databases aren't that helpful anymore … You need alternative methods to start classifying these rare variants, because rare variants continue to occur no matter how much testing you do."

Quest declined to provide an estimate of how many people it has tested for BRCA mutations since launching its BRCAvantage test in 2013, but highlighted that across its entire lab business, the company tests 500,000 people daily.

Myriad, meanwhile, often highlights the size of its proprietary database and the volume of patients it tests for BRCA mutations as a key advantage over competitors. According to company spokesperson Ron Rogers, Myriad runs more than 200,000 tests per year.

The company has also been quite vocal in highlighting the problems with public variant databases and has cautioned labs and healthcare providers against using these resources to make clinical decisions. Researchers from Myriad recently published a study comparing variant classifications across five databases — BIC; the Leiden Open Variation Database 2.0 (LOVD) in the Netherlands; ClinVar (the database associated with NIH's ClinGen effort); Inserm's UMD; and the Human Gene Mutation Database in Cardiff.

The analysis, published in the Journal of Community Genetics, retrospectively analyzed 2,017 BRCA variants, of which 116 were identified as pathogenic in at least one database. However, of these 116 variants, all the databases agreed on the classification for only four. Meanwhile, 34 percent of the mutations that Myriad identified using its own database didn't show up in any of these other repositories.

For 18 markers that Myriad deemed particularly challenging to classify, UMD and LOVD "performed the best" in supporting why they classified certain markers as pathogenic using literature references. ClinVar and BIC performed poorly in this regard, according to Myriad's analysis. Still, Myriad has reservations about the quality of the data in Inserm's database. "In terms of the Quest/Inserm collaboration, their press release indicates it is a 'fee-for-service' subscription database," Rogers told GenomeWeb over email. "I am not sure how much value Inserm would add to the data that Quest and LabCorp could access from public databases."

While Myriad doesn't have much faith in public databases, having stopped submitting to BIC in 2004, Strom said BRCA Share would be happy to have Myriad as a contributor. "All labs are welcome," he said. "If [Myriad] decided the war is over and [they] want to participate, all they have to do is be willing to upload all their variant data past, present, and future … and we'd probably have to hire more curators."

While Strom agrees with Myriad's assessment that ClinVar and LOVD aren't yet ready for clinical use, as far as publicly accessible databases go, Quest has determined UMD to be a cut above the rest. "That's why this whole effort started," he said. "When we looked around the world, UMD was head and shoulders beyond all the other publicly available databases in terms of its clinical utility. And we decided to not try to reinvent the wheel."

But in advancing BRCA Share, Quest doesn't want to discourage others from submitting to public resources, such as ClinVar and LOVD. In fact, for several years now, Quest has been working with LOVD to develop a way of uploading its own data, and finally achieved it a few months ago. He said Quest will soon submit variant information into LOVD.

Quest had also committed early on to upload data into ClinVar, but hasn't yet. "ClinVar requires its own software in order to upload data, and our IT systems are extremely complex," Strom said. "I was naïve at first and thought I could just turn the spigot on." After looking further into such databases, he has a better appreciation for their complexity. "To take a backlog of several thousand cases and upload them correctly into a database is not at all trivial," he said.

He noted that LOVD and ClinVar may be collaborating in the future and if they do, Strom hopes that by submitting to LOVD, Quest's data will end up in ClinVar without duplicative effort. For now, he thinks BRCA Share and other efforts, such as ClinVar, can coexist.

"I liken this to the [Human] Genome Project, where you had the public effort [which] was extraordinarily expensive and it took a lot of effort," Strom said. "Then you had Celera that came in with a very focused private effort and was actually able to achieve pretty much the same goal. Then, eventually, they merged. I see this as that."

However, Strom emphasized that BRCA Share is "not about exclusivity. … There have been some snide comments that this is about limiting access. It's quite the contrary," he said, noting that academics, support groups, and patients can access BRCA Share for free. "All we're asking is that laboratories that are making money doing BRCA testing pay their fair share."

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