VUS stands for Variant of Uncertain Significance, or Variant of Unknown Significance, or sometimes Variant of Unclassified Significance.
The management of VUS’s has become a major source of confusion in genetic medicine in recent years. Genetic testing laboratories are uncertain how, or which, to report. Doctors are uncertain how, or which, to act upon.
This week we heard about an alleged incorrect management of a VUS that has resulted in a $1.8 million medical malpractice lawsuit. It is unlikely to be the last. This is a rapidly increasing problem. We need to address it.
What is a VUS?
What is the definition of a VUS? There isn’t one. This is part of the problem. Calling a variant a VUS is a classification of exclusion. Labs work hard to find variants with a high chance of causing disease (either >95% or >90%). Such variants are called ‘pathogenic’ or ‘likely pathogenic’. We also work hard to identify variants with less than 10% chance of causing disease. Such variants are called ‘benign’ or ‘likely benign’. Any variant that doesn’t fulfill either of these is typically called a variant of unknown significance, without further categorisation. That’s all variants between 10% and 95% chance of having clinical impact! Do we really have no other information to offer on this large number of variants?
Most VUS’s are benign
We know a lot more about this very large group of genetic variants than we are communicating. As I have described in previous blogs, we now know that rare genetic variation is common and mostly harmless, and that all variants should be considered innocent unless proven guilty. The vast majority of the variants in the 10%-95% VUS group will be at the lower end. Indeed if one integrates all the available information about how variants cause disease we can move most of them into the <10% ‘likely benign’ group, as I previously showed for the gene PALB2.
Unfortunately, comprehensive knowledge integration to inform variant interpretation is not done routinely, nor systematically. We rely too much on information pertaining to the specific variant. This means if the variant has not been reported before it is often called a VUS, irrespective of what other information might be available. Indeed the Wikipedia definition of VUS is ‘this category is for variants that have not been reported previously’.
VUS’s are often mismanagedThere are many examples and numerous studies showing that VUS’s are not being managed appropriately. Far too often they are managed in the same way as a pathogenic variant; they are being managed as guilty, not as innocent until proven guilty. Very serious harms are regularly occurring as a result, and this will only increase as genetic testing becomes more widespread. This over-management occurs despite clear recommendations that a variant of uncertain significance ‘should not be used in clinician decision making‘.
Why is this over-management occurring despite the guidelines? The typical response from genetics is disbelief, dismay and disbarment: “How is it possible those non-geneticists treat a VUS as a positive result? It’s shocking. They shouldn’t be allowed to do it at all. Clearly, only genetics are capable of doing this”. There is scant consideration that we might be part of the problem. Or that changing what we do could be part of the solution.
It is possible that VUS management is just too difficult for medical practitioners to understand, but it doesn’t seem likely. Doctors are adept at distilling, handling and communicating complex information. Particularly information involving uncertainty. Communicating about uncertainty, guiding decisions in the face of uncertainty is the heart of medicine.
If medical practitioners are not taking the correct meaning from the information we are giving them, it is likely because we are failing to communicate that meaning correctly. We should at least consider this possibility. We need to share the responsibility for the failures of the current system and look inwards as well as outwards for solutions.
VUS – Very Unhelpful Statement
So what do we communicate about VUS’s? Typically some variation of the following sentence will appear on the report.
‘A variant of uncertain significance was identified. Currently there is insufficient evidence to determine whether this variant is pathogenic or benign’.
This is a Very Unhelpful Statement. It nominally discharges the responsibilities of the report generator, but places the report receiver is a very, very difficult position. Anyone receiving such a report would assume from this statement that there is a chance that the variant is pathogenic. They are forced to make their own judgement about how likely that is.
People might reasonably assume the chance is fifty-fifty. Or they may well think the chance of the variant being pathogenic is higher, otherwise why has the report taken the trouble to mention the variant at all? Generally medical reports do not list all the things that are unlikely to be relevant, so it is understandable why the report receiver might draw this conclusion.
We are driving VUS mismanagementSo it should come as no surprise that people are over-estimating how likely a VUS is to be pathogenic. Or that they are managing VUS’s in the way they are managing pathogenic variants. And I include geneticists and genetic counsellors in ‘people’ here. I have seen many, many situations where geneticists have got themselves in a tricky position over VUS management.
It is not so easy to have a detailed conversation with a patient about something, and then say it’s probably nothing, and we are not going to do anything about it, forget I even mentioned it! This is not a good interaction for either party.
So the genetics team might suggest some gentle change in management because of the VUS. Perhaps extra screening if it is a VUS in a cancer predisposition gene. Nothing too harmful, just something to make both patient and counsellor feel better. But now the VUS has been labelled as sufficiently suspicious to warrant screening, and it becomes almost inevitable that someone will raise the option of risk-reducing surgery. Before you know it an entirely healthy person has had healthy parts of their body removed for no justifiable reason. And then their relatives start asking if they should do the same thing……
Changing VUS management
It is clear that the current system drives VUS mismanagement. And that the problem starts with how genetics handles and reports VUS’s. We are driving over-management. We are driving people, both patients and doctors, to believe that managing VUS’s as pathogenic variants is the ‘to be on the safe side’ approach.
In next week’s blog I will discuss potential ways we could change how we handle and communicate about VUS’s that could help to alleviate this serious problem.