As a healthcare provider, you most likely hope for a genetic testing result that provides some kind of clear answer about what to do next. However, sometimes genetic testing will reveal a variant of unknown significance (VUS), which can be a challenge for both you and your patients. These variants are sort of “innocent until proven guilty” and more evidence is often needed before we can determine if these variants are disease-causing (guilty) or benign/normal variation (innocent). Genetic testing laboratories should have a defined process to regularly review the evidence for genetic variants, so they can eventually come to a verdict and provide a more clear answer. This is often referred to as the “variant review process”. But what does it really mean when a lab says they regularly review genetic variants?

Here are 5 things you should know about the variant review process at Ambry:

1. How often does the variant review process occur? Daily! When a genetic variant is identified, it is reviewed and interpreted if it has not been seen or reviewed in the last 6 months to a year as we prepare the genetic testing report. Additionally, we have weekly meetings with a multidisciplinary team to review variants eligible for reclassification, so that we can discuss the available evidence and decide if we can come to a verdict regarding the variants impact on disease (innocent or guilty?).  
2. Who is involved in this process?   Ambry’s clinical reporting team, which includes genetic counselors, PhD variant scientists, and laboratory directors is involved in the daily review of variants as they prepare testing reports. Additionally, our team of variant scientists, who has a unique expertise with the variant classification process, is involved. This team includes PhD scientists and genetic counselors who work with structural biologists and statisticians   to review and approve variants that are eligible for reclassification from VUS to a clinically actionable result. The evidence is also reviewed with our senior lab directors (the judges) for consensus and approval of any reclassifications.
3. How do we decide which variants to review? When enough evidence is available for a variant of unknown significance, as indicated by Ambry’s variant classification scheme, that variant becomes eligible for reclassification and will be discussed during the variant review meetings if it will be clinically actionable. Variants that meet criteria for being classified as clinically benign are reclassified daily by our clinical reporting team.
4. What type of evidence is reviewed during this process? There are multiple types of evidence that may be reviewed, and the exact pieces that are available will depend on the particular variant. We leverage Ambry’s robust clinical database, which includes patient clinical and family history information, segregation data (how is the variant tracking in a family), de novo events (how often is a variant new in someone for the first time in a family) and co-occurrence with other known mutations. We also sometimes utilize unique data from Ambry’s Translational Genomics lab, structural biology data, and statistics. These additional pieces of evidence can be key for reclassifying rare genomic variants, which account for the majority of VUS. For some very rare variants, we even work with researchers and other laboratories from around the world to try and clarify their significance.
5. How is a final decision made and what happens next? Once the evidence is compiled, each line of evidence is carefully reviewed, then weighed and combined based on Ambry’s variant classification scheme to make a final decision.  This classification scheme is in line with the American College of Medical Genetics criteria, but is unique to Ambry. It has evolved over time with our years of experience and our work with international expert groups to include many gene specific nuances. We know that one set of rules can’t apply to so many different genes, so there are gene-specific criteria that we apply. Once a variant is reclassified, we start the process of updating patients by providing an amended report to the ordering healthcare provider for clinically actionable (guilty) variants or a reclassification notice for variants being downgraded to likely benign or benign (innocent).

Overall, genetics is complex and sometimes the answer isn’t clear right away. However, our expert scientists are trained to critically review and question everything, which is what takes place during this variant review process. We are constantly reviewing what we think we know and understand. At the end of the day, it is all about bringing clarity and finding answers for patients and families to guide personalized medical management. We will not stop until human disease is understood.