Commercial, academic and non-profit laboratories are using the availability of additional genes in a single panel as a marketing tool - a ‘more is better’ approach. In the United States, the rapid uptake of multi-gene tests may be partly attributable to the highly commercialized nature of medicine and health care, increasing the likelihood of competitive pressure resulting in tests being introduced into clinical care before there is a well-established evidence base for optimal use [53],[61]-[63]. While the VUS rate should drop over time, the prospect of dealing with many VUS results will confront the system immediately and for the foreseeable future [3],[4],[36]. Healthcare providers and patients will continue to face uncertainty while making life-changing decisions about treatment. With current and future patients in mind, how can we lower the VUS rates as fast as possible?

The key to improving the interpretation of VUS results, and thus lowering the overall VUS rate, is the accumulation and organization of high-quality data and the development of robust methods for data interpretation. The data will come as a result of testing large numbers of patients and following up on their clinical outcomes. In the case of BRCA1/2, Myriad’s previous patent position led to the company performing the vast majority of testing in the United States. This allowed Myriad to accumulate and collate genomic, pedigree and clinical data, enabling them to maintain the lowest VUS rate achieved so far. Myriad contributed to the BIC database until 2006 (with their last large data contribution in November 2004), but thereafter maintained a proprietary database, largely inaccessible to academic researchers, non-profit organizations and the patients who had sent their samples for analysis.

The situation for multi-gene panels and WES/WGS will be different because there are many genetic testing companies on the market already offering their own gene panels or sequencing services. Competition among companies has led to more competitive pricing, but also to multiple places in which data are held, some of which may remain proprietary and therefore not widely accessible. We suggest that the fastest way to accumulate data and lower VUS rates is to ensure that all of the data eventually go to one accessible place. How can we encourage this outcome in a competitive marketplace?

A significant part of the solution to this problem is the creation of a centralized database for gene variants. This does not imply that all data of all kinds should be in a single database; rather, we suggest the creation of a database designed for clinical use containing the core data used by those interpreting genomic variants. Reclassification of variants happens using a variety and combination of methods, including functional assays, pedigree/family histories and statistical analyses. The importance of a centralized database is in the convergence of these many pieces of data for a meaningful and accurate reclassification of VUS, although even a large centralized database does not eliminate the need for additional clinical interpretation, statistical analyses and further research. The ClinVar database, an open-access National Center for Biotechnology Information (NCBI)-funded resource connecting genome variations and phenotypes, has the potential to fulfill this role [64], in a similar manner to the BIC and others [31], but with a clinical focus that also includes a greater range of genetic disorders. However, its construction faces a number of ethical, commercial, legal and logistical obstacles. Some of the legal and ethical issues concern the maintenance of patient privacy and ensuring informed consent. ClinVar and the laboratories and research institutions collaborating with and contributing to it are working to address these issues. From an intellectual property perspective, why would entities with monetary or commercial interests be willing to share proprietary information? The main logistical issues concern the lack of existing infrastructure for data sharing, the development of interpretive algorithms, and obtaining funding to maintain the database.

There are currently many groups working to address some of these data-sharing issues, particularly by creating repositories in which data can be collated [15],[64]-[69]. Such efforts have not yet converged on a single centralized database, although as previously mentioned, ClinVar may emerge as the main hub for clinical interpretation. These efforts have also been hindered because not all databases are up to date and reliable, and some locus-specific databases are small operations [31],[70]. This is unsurprising given that many of the databases were established to enable research, and funding is unstable or insufficient to support use as a reliable clinical tool. Policies that create incentives for participation in public databases are the most promising way to expedite clinical interpretation of genomic data in the long run.

Competition in the genetic testing market means that insurance companies, health plans and other payers (government or otherwise) have a strong influence. The degree of competition in genetic testing depends on how a healthcare system is organized. BRCA testing in the United Kingdom, for example, remained largely under the auspices of the National Health Service, despite Myriad’s UK patent rights [71]. In Canada, Myriad’s effort to enforce its patents through its licensee was resisted by the Health Ministry (and ultimately the Premier) of the Province of Ontario, which refused to force its provincial health system to stop BRCA testing. Myriad never sued, so in effect Myriad’s patents in Canada have not been enforced [72]. Children’s Hospital of Eastern Ontario recently filed a lawsuit contesting patents on genes associated with long QT syndrome [73]. One purpose of the litigation is to clarify Canadian law on whether genes can be patented. And in Australia, laboratories under the provincial health systems continue to offer BRCA testing under a voluntary agreement by the BRCA-testing licensee [74]. A recent review of the effects of patents on genetic testing in Australia paints a nuanced picture and cautions ‘against extrapolating [views on effects of patents on genetic testing] survey results from one jurisdiction to another’ [75]. The role of patents thus differs among jurisdictions, but the central importance of pooling data and sharing methods is global.

Policy change could encourage the sharing of data needed to make and verify clinical interpretations of genetic variants. For instance, a requirement for reimbursement could be that laboratories offering tests must share sufficient information about methods and sufficient data for independent verification of results and interpretation. Such a policy could be an effective method of encouraging laboratories to contribute to public databases and to share their interpretive algorithms. Another policy option is to pay directly for interpretive services, but only on condition of sufficient disclosure to enable independent verification. These policy changes could be implemented either as criteria for accreditation (such as those set by the International Organization for Standardization (ISO) in much of Europe; Clinical Pathology Accreditation (CPA) in the United Kingdom, although CPA accreditation is currently being transitioned over to ISO; laboratory accreditation under the College of American Pathologists), certification of health professionals (such as those set by the Clinical Laboratory Improvement Amendments in the United States), or as a condition of laboratory reimbursement stipulated by insurers and health plans that pay for the tests [12],[16],[76],[77].

How and when to re-contact patients if new information emerges could also become more consistent as a matter of policy. One option is the effective implementation of EHRs, in which a patient could directly update contact information on a single record that stays with him or her, regardless of the specific healthcare provider. This would, however, also require the integration of clinically relevant genomic data into the EHR, which remains a challenge. Even with the infusion of public funding, the implementation of a well-functioning, reliable EHR system requires significant additional investment, and wide-scale implementation has proved to be difficult [62],[78]-[80]. Informed consent procedures that clearly indicate that it is a patient’s responsibility to periodically check back in with their provider after a VUS result would put the onus on patients, and avoid some of the pitfalls of patients changing address or changing physicians. Another option is to design a database that manages genotypes and phenotypes so that interested patients can search for updates themselves. In the event of a reclassification, they could re-contact their healthcare providers to discuss further options. Direct consumer use of genotype databases would, however, present a daunting technical challenge because users would require a simplified interface designed for infrequent and non-expert users, not just for genetic professionals. The Patient-Centered Outcomes Research Institute (PCORI) has announced plans to spend US$100 million building PCORnet to empower individuals and families to participate in research. Several genetic organizations have joined early efforts to harness this power, including PCORnet, the Genetic Alliance, Facing Our Risk of Cancer Empowered and DuchenneConnect [81]-[84]. These efforts will help pave the way to stronger patient engagement, and will provide lessons on how best to manage patient re-contact, informed consent and access to clinical data and databases.

Another important policy to improve the clinical interpretation of genomic variation is arguably the most important of all: continuing support for research efforts that have been sustained for three decades on developing methods for functional biological analysis, fostering bioinformatic methods, and detecting such variants. These efforts are global, and include networks in Europe, North America and Asia, and increasing attention to ‘translational’ research efforts, in moving from genomic discovery to clinical utility.