NEW YORK (GenomeWeb) – ClinGen, an NIH-funded resource that aims to define the clinical relevance of genes and variants in precision medicine and research, has published a list of labs that meet certain requirements ensuring the quality of data they've submitted within a public database.
The list is intended to provide users of ClinVar — an archive of freely available information on genotype-phenotype relationships — a level of assurance about the variant classification data submitted by clinical labs. Although submissions to this database has increased significantly since NIH launched it in 2013, some in the genetic testing industry have criticized the resource for containing incorrect information derived from low-quality labs. Others worry that when healthcare providers look up a genetic variant their patient has in ClinVar, they may trust inaccurate or outdated information that leads them down a wrong diagnostic path.
Heidi Rehm, principal investigator of ClinGen, hopes that this list, so called "Clinical Laboratories Meeting Minimum Requirements for Data Sharing to Support Quality Assurance," helps diminish these concerns about ClinVar and incentivizes labs to commit the resources necessary to responsibly submit and share their data within the database. One major motivating factor might be that insurance companies and healthcare providers are interested in using the list as a way to decide which labs to reimburse and order tests from.
In order to be on the list, first, labs have to have received one star from ClinVar, indicating they have outlined the criteria they use to make assertions about variants submitted to the public database. Labs also have to submit new variants and update reclassified variants to ClinVar at least once a year; submit all categories of variants (pathogenic, likely pathogenic, variants of unknown significance, etc.) they return to patients; attest to submitting at least 100 variants and at least 75 percent of them in the past year; and have CLIA certification or meet equivalent standards in another country.
Finally, in order to be considered by ClinGen as a lab that shares quality data within ClinVar, these labs also have to be registered and have an up-to-date listing in the Genetic Testing Registry — an NIH database that the public can reference for information about the clinical evidence underlying marketed tests.
For years, Rehm, who is director of the Laboratory for Molecular Medicine (LMM) at Partners Healthcare Personalized Medicine, has been spearheading efforts to make data sharing on genomic variants a standard practice among labs. Public transparency about variant interpretations, she insists, is the way to ensure that patients are receiving the best answers about what their genetic testing results mean in the context of health and disease.
Rehm has not only had success in encouraging labs to submit to ClinVar, but in getting peer-reviewed journals to require data sharing for publication; the US Food and Drug Administration to consider requiring labs to submit as a condition for regulatory approval; providers to order tests from labs that share data; and at least one insurer, Aetna, to make data submissions a condition for coverage in the context of BRCA testing.
ClinGen is advancing the new clinical labs list as several other large, national insurers have agreed to use it to determine whether they will cover genetic testing provided by certain labs, according to Rehm. In a commentary published in Genetics in Medicine, Rehm recently noted that data sharing has increased among genetic testing labs and this activity is actually improving the quality of their variant interpretations.
"I am now seeing a strong correlation between the quality of interpretations and whether the laboratory is a ClinVar submitter," she wrote. "I have also personally watched laboratories dramatically improve their interpretation methods after engaging in active data sharing in ClinVar."
So far, 10 labs have met ClinGen's minimum criteria for inclusion in the list including Ambry, ARUP, Center for Mendelian Genomics, University Medical Center Ljubljana, Counsyl, EGL Genetics (Emory), GeneDx, Illumina, Invitae, LLM, and the University of Chicago.
Labs can receive additional "badges" for exceeding the basic requirements, for example, if they submit evidence for the majority of their variant classifications in ClinVar; ensure that 75 percent of their variants were submitted in the past five years; engage in efforts with other labs to resolve classification discrepancies in the data repository; and provide a way for patients to consent to sharing individual-level data.
All 10 labs have badges indicating they are resolving variant discrepancies with others in the field. Some of these labs, after they submitted data to ClinVar, have worked to resolve discrepancies and were able to achieve concordant classifications for the majority of the variants that had conflicting interpretations.
GeneDx, Illumina, Invitae, and LLM also have a badge for submitting evidence underlying the majority of their ClinVar submissions. Three labs — Invitae, GeneDx, and LMM — have all four badges.
According to Rehm, many labs may not yet have committed resources to prioritize submissions to ClinVar. But by aspiring to get on this list and win badges, labs can start fresh.
One of the basic criteria is that a lab submit at least 75 percent of variants reported in the past year, but labs aren't being required to share their older interpretations to get on the list given that some labs are still getting a system in place to share their data.
Ideally, Rehm wants to see labs sharing data going back five years, which she estimated is around the time the field started amassing good publicly available data on the population frequencies for genetic variants. In the GIM commentary, she points out that in recent years updated American College of Medical Genetics and Genomics' guidelines, established nomenclature for classification categories, and the establishment of ClinGen and ClinVar has brought more consistency to variant classification activities.
Many labs haven't submitted to ClinVar, arguing that the repository is nothing more than a dumping ground for variant data that's error prone and inconsistent, and its use could potentially harm public health. An oft cited figure is that 17 percent of variants submitted to ClinVar by multiple labs disagree in their classification. However, Rehm and commercial labs like Invitae, which have invested the resources to submit to ClinVar and work with other industry players to resolve discrepancies, argue that ClinVar is necessary to highlight classification discrepancies and improve the quality of interpretations.
"While I am inherently biased in my views as a funded ClinGen investigator … I think the rapid growth and usage statistics for ClinVar, and the absence of any documented harm whatsoever bring an objective view that the database has become an invaluable positive asset," Rehm wrote in the GIM commentary. But there is much room for improvement.
For example, ClinVar currently lists labs according to the number of variants they've submitted, but within the database users can't fully discern the spectrum of variant data they've submitted. "A brand new lab that's submitting everything might have the same number of variants submitted as a very large, established lab, that only submitted the BRCA1/2 genetic variants because that's what Aetna required for reimbursement for that test," Rehm said.
Variant submissions are distinguished within ClinVar by a star system, though this system doesn't indicate whether an interpretation is inaccurate. Using this system, individual labs can get one or zero stars for submissions if they've provided interpretation criteria, and when submissions don't have any discordance, they get two stars. When a submission has been reviewed by a ClinGen-approved expert panel, it gets three stars, which overrides interpretations by individual labs. And when a submission has been reviewed by a practice guideline body, it gets four stars.
Rehm pointed out in the GIM commentary that currently within ClinVar it's easier to understand the distinction between a three- or four-star submission and a submission with zero, one, or two stars. However, the difference between a submission that has zero stars and one star is not so clear.
In an effort to offer the public more clarity on the trustworthiness of variant submissions, ClinGen is going to have its own representation of ClinVar data, where it will remove incorrect interpretations and make it more clear when a single-star submission overrides a zero-star submission, according to Rehm.
While the quality of publicly available variant interpretations continues to improve, other stakeholders in the healthcare space can do more to encourage data sharing, in her view. In particular, Rehm called out the College of American Pathologists, which accredits most genetic labs, to make submissions to ClinVar a requirement for assuring lab quality.
As for clinical labs and researchers, "Enough said," Rehm wrote. "It’s time to submit your data!"
The majority of labs, including the two largest US reference labs, Quest Diagnostics and Laboratory Corporation of America, aren't yet on the data-sharing quality assurance list put forth by ClinGen. "But these labs have conveyed back to me that they're working toward meeting the criteria, and they have plans to get all their content submitted to ClinVar," Rehm said. "I'm excited about the positive impact of getting this list out there."