VUS iz dos? Suggestions For A Reasonable Policy On Reporting Genetic Variants of Unknown Significance.

In a previous post, I raised questions about the appropriateness of certain billing policies for multigene cancer panels. As expected, it evoked some thoughtful and strongly felt comments and disagreements. But one thing we can all agree on about multigene panels is that the rate of detecting variants of uncertain significance (VUS) is way too high, usually in the range of 30-40%.

It will be many years before we will be able to determine the clinical significance of most of these variants, even if collaborative VUS reporting among labs becomes a reality and – more concerning to me – the public databases are properly curated. Indeed, the high frequency of VUS may prove to be the Achilles heel of multigene panels particularly as genetic testing increasingly takes place outside of the realm of genetics specialists.

What benefits do patients get from knowing about VUS? Absolutely none that I can think of. Knowledge of a VUS does nothing to enhance their medical decision-making or psychosocial well-being. For some patients, knowledge of VUS may contribute to short-term anxiety and uncertainty. Despite our best efforts, many patients have a look on their face that suggests something along the lines of “I am not exactly sure what was just said to me but I think I have a mutation in a cancer causing gene and how can that not be related to my family history of cancer?” Even more concerning, we all have one too many stories about patients who made surgical decisions based on a VUS, particularly when patients have not been counseled by a genetically sophisticated clinician, in direct contradiction to our dictum that “These results should not be used to guide patient care or cancer risk assessment for the patient or the patient’s family.”

So let me offer a solution that many genetic counselors will think is heresy and antithetical to basic genetic counseling philosophy. Stone, spitball, egg, and tomato me if you will, but my recommendation is that VUS should not be reported out by laboratories.

Instead of reporting specific VUS, I suggest that all genetic test reports – and pre-test counseling notes and result letters that are sent to patients and care providers – include a clearly written and highly visible general disclaimer along the lines of: Variants of unknown clinical significance are very commonly detected on genetic tests. These variants cannot and should not be used to guide medical care or help better understand cancer risks, and therefore are not detailed here. We continually monitor and study these variants. In the uncommon event that a variant is eventually re-classified as pathogenic or otherwise important for guiding your medical care and assessing your health risks, you and your doctor will be promptly notified.

A variant  should be reported when the lab feels that there is a reasonable possibility that the variant might be clinically important. In those cases, labs should offer family studies if they think that the functional and clinical significance of the mutation can be clarified by studying families that segregate the specific mutation. Of course, labs should be able to provide the VUS result – along with their rationale for classifying it as unknown rather than benign or pathogenic – if a patient or provider requests it.

By the way, I prefer Variants of Unknown Significance over Variants of Uncertain Significance. Maybe I am nit-picking, but uncertain seems to leave more psychological wiggle room for patients and care providers to think “Hey, maybe this is important” while unknown suggests that we really do not know what it means.

I can think of two reasons that help explain why we continue to report VUS to patients. One reason stems from our tendency to over-explain, the original sin of genetic counseling. In our desire to adequately inform patients we often overload them with a compressed course in advanced biology and genetics. In a form of counter-transference, we think of our patients as some version of ourselves and we sometimes unconsciously speak to them as if we were speaking to ourselves. Many genetic counselors are science nerds at heart and we tacitly assume that any rational person (i.e., someone who thinks like me) would want to know all those gloriously fine technical and scientific details.

The second reason that we report out VUS is that our concept of a gene is stuck in about 1995 or so. Back then we envisioned genes as highly stable structures which would occasionally have a few mutant alleles, and therefore Mutation = Bad. In fact, mutations are strikingly common and only a few are of clinical or evolutionary significance. Mutations are the norm for genes, not the exception.

This policy would require broad acceptance by the genetics community – genetic counselors, medical geneticists, genetics labs, and others. Perhaps a first step could be to conduct studies that randomly assign patients to two groups, one that receives VUS results and one that does not. Those patients could be followed for a period of time and then compare the two groups for differences in utilization of surgery and screening, as well as psychosocial adaptation and quality of life.

Let’s modify our counseling philosophy to fit into the 21st century. Many of us may kick and scream at first because, well, it is so different from what we normally do. But once you get past the initial shock,  relax and kick off your shoes, sip a beer, and think about it more clearly and calmly, you may begin to feel differently.


Filed under Robert Resta

11 responses to “VUS iz dos? Suggestions For A Reasonable Policy On Reporting Genetic Variants of Unknown Significance.

  1. Marilyn J. Erickson, MS, MPA

    Interesting thought regarding the non-reporting of VUS. I do sometimes wonder why we stress about the VUS reports on the cancer panels (although risk of cancer versus risk of autism can result in different emotional responses) when there have often been one or more VUS results on Microarray testing. As the years have gone on, access to the “old” variants has been valuable as every so often there is a previous VUS now associated with developmental delay, or autism, or . . . and as families move around, relying on the labs to reinterpret and notify can be challenging. I remember even before microarray, prenatal karyotyping would result in inversions, or rearrangments with unclear significance at a higher frequency that we sometimes liked, especially when testing was done for sonogram abnormalities. This interpretation of uncertain results is what genetic counselors are trained to deal with. I do not think non-reporting should be an option, rather remember this is how new technology first appears, messy unclear, and challenging.

  2. Sarah Keilman

    This is such an interesting though Bob, I’m very curious to see where we end up with VUS’ in a year or two. I actually think this change would have a lot of benefits.

  3. Anne Madeo

    >We continually monitor and study these variants.

    This is the sticking point for me. What is the antecedent to the pronoun, “we,” in that sentence? I see labs as having some responsibility for monitoring and studying. But even in the unlikely event that a variant is identified as pathogenic (or not), do they report the new interpretation to the ordering provider? That’s what you seem to be suggesting below:

    >In the uncommon event that a variant is eventually re-classified as pathogenic or otherwise important for guiding your medical care and assessing your health risks, you and your doctor will be promptly notified.

    However, I don’t think it’s practicable for clinicians to follow patients like that (perhaps a function of the patient population I see). They’re transient and even patients who stay in the same town may have moved 5x since the last time I saw them and changed cell phone numbers 3x. Morever, what if the ordering provider is no longer with the facility?

    I like the idea of not reporting VUSs, as my experience has been similar to your description of the patient who just received a VUS report, ““I am not exactly sure what was just said to me but I think I have a mutation in a cancer causing gene and how can that not be related to my family history of cancer?” I’m just not certain how patients can get the right follow up care as ‘studying and monitoring’ happens.

  4. Danielle LaGrave, MS, LCGC

    As a lab GC (working with arrays, not next gen panels), I do feel your pain. However, I think the solution is not “do not report”. Commercial labs cannot fund the constant reassessment of VUS calls and the efforts to re-contact in cases where a variant call was changed from VUS to either benign or pathogenic would be daunting. I have trouble reaching the actual ordering provider of a test half the time, and this is when the test was ordered days or weeks ago! And even then, it is amazing how often the patient is not in the care of that provider. For example, testing was ordered by a resident, and I get the attending who has no idea who this patient is, or why testing was ordered, and the patient is discharged, and the resident is off this week or has changed facilities (July is a bear, I can tell you!). Or I get “genetics told us to order this, but we don’t know anything about it”. Or an OB orders the test on the partner of a patient, and cannot track him down without the woman’s name… but of course they don’t PROVIDE the woman’s name anywhere on his order. I cannot imagine trying to reach a provider years after the test was performed and have them be able to reach the patient, understand why I am calling and giving a hoot (I do find that there is an appalling lack of apparent “caring” about these test results in many offices).

    If you take it as truth that commercial labs cannot routinely reassess and re-contact patients/providers, then think what would happen if we did not report VUS calls. If we did not report variants then providers and parents would not know that the child carries a deletion or duplication that may (or may not) be a contributing factor to the child’s phenotype. If that VUS is later determined to be pathogenic, they will not know that they have an answer, and they have no way to know without getting a new array every few years so the newly characterized pathogenic del or dup can now be reported by the lab.

    I have no easy answer to your concern. And I agree it is a valid concern, but perhaps one that may be more of a growing pain than a killing blow. Genetic counselors are trained to help patients understand and absorb this information. This is just another reason why our profession is needed more and more as time and technology progress.

  5. I agree with a couple of the previous posts that although we all struggle with the value of reporting VUS, the challenge to what you suggest is that it puts too much burden on the labs to re-contact – this can be financially and logistically challenging. But I just want to add that I ABSOLUTELY affirm your preference for the term “Variants of Unknown Significance” rather than “Variants of Uncertain Significance.” It may be nit-picky, but choosing our terminology carefully can help provide some clarity to patients and non-genetics health care professionals.

  6. David Tran

    While I empathize with the confusion and anxiety that VUS reporting causes, I would rather have all the results from a screen/test. To me, the situation is similar to a full workup for a physical, I can get a print out the results for all the screens that were done: blood glucose, urine test etc. Say I had gotten some borderline results but the doctor said let’s monitor the situation. I may not understand what reactive C protein is but at least know what the results were.

    Now imagine if those results were only reported if over/under a diagnostic threshold. Perhaps I can trust my doctor to make note of borderline values. But then I might change doctors. Or the doctor has too much to do and forgets to monitor my situation. I would much rather have the data up front because I’m the one with most vested interest in my health.

    Suppose I had gotten a screen from a company without VUS reporting. I have a printout that says negative results, but there are unreported VUSs. In 5 years I have a child, and that child is diagnosed with a hereditary disease. I hope I can call up the company and get my full results. But what if the company folded, or was bought out? And my data is lost in the shuffle.

  7. Amy Decker

    My first reaction to the concept of not reporting any VUS results was-wow, that would leave many a lab GC (myself included!) out of a job! Of course, this may actually lead to a significant increase in testing; patients/providers may request to have testing every few years for the same genes/panels because VUSs are reclassified all the time. So if we are not reporting them, I guess you have to keep checking for them, as you would never really be sure if/when a variant has been reclassified.

  8. Colleen Caleshu

    Interesting and provocative as always Bob. What strikes me is that we, as clinical genetic counselors, can actually do something very similar on our end.

    As a cardiovascular genetic counselor I have lived with the long lists of VUSs that come with next-gen multi-gene testing for many years. I gradually shifted my practice to tell all patients up front “we will find something, if we ran this test on me or your cardiologist we would find something, what matters is if we find something that we can be confident caused your heart problems.” As you mention, we need to embrace just how common and normal very rare variation is and we need to normalize that for our patients. Post-test, I find my patients respond very differently to VUSs given that pre-test discussion (“oh, well you told us the test would find things”). I also have shifted my post-test counseling to really de-emphasize VUSs. If a pathogenic variant was not found, then I will discuss that and the implications (eg. lack of predictive genetic testing for family members) with the patient for some time, then later mention that one, or more, inconclusive variants were found, just as we expected. We’ll keep an eye on them, but for now they don’t help us much. It all frames a VUS as “unrelated until proven otherwise” instead of “probably pathogenic until proven otherwise”.

    Personally I am far more in favor of this approach than not including them on the report. I’ve had cases where a highly suspicious VUS caused us to look for a particular phenotype. And what about collaboration between the clinical group and the lab for the purpose of segregation analysis? Or the fact that when patients are asked if they want inconclusive results they say that they do. Just a few reasons to keep them on the report.

    What matters is how we think about them and how we talk about them.

  9. Heather Newman, MS, LCGC

    I am in the process of writing up an article about an experience my team recently had in dealing with a patient who latched onto a reported VUS. I am wondering if you, Bob, or if anyone else knows of published articles that discuss this “to publish, or not to publish” issue in the literature. Thanks!

    • Heather Newman, MS, LCGC

      Sorry, this “to report, or not to report” issue.

      • Robert Resta


        I have not done a thorough lit search on this topic. To some extent, Angus Clarke discusses it in: Managing the ethical challenges of next-generation sequencing in genomic medicine.
        Clarke AJ.Br Med Bull. 2014 Sep;111(1):17-30. doi: 10.1093/bmb/ldu017. Epub 2014 Aug 13.PMID: 25122627.

        In microarrays, there is this study of parent and provider preferences:Preferences for results from genomic microarrays: comparing parents and health care providers.
        Turbitt E, Halliday JL, Amor DJ, Metcalfe SA.Clin Genet. 2015 Jan;87(1):21-9. doi: 10.1111/cge.12398. Epub 2014 Apr 29.PMID: 24773164

        And the commentary in the discussion section of this article:
        Large numbers of individuals are required to classify and define risk for rare variants in known cancer risk genes. Shirts BH, Jacobson A, Jarvik GP, Browning BL.
        Genet Med. 2014 Jul;16(7):529-34. doi: 10.1038/gim.2013.187. Epub 2013 Dec 19. PMID: 24357849

        I would be interested to hear about other publications on the topic.


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