Tag Archives: VUS

by | April 12, 2015 · 11:17 PM

Do I Really Have To Tell Them? Duty To Recontact And Variants of Unknown Significance

Duty to recontact (DTR) is one of those principles that on Mondays, Wednesdays, and Fridays I feel should be an unquestioned standard of care. On Tuesdays, Thursdays, and Saturdays, the practical part of me prefers to sweep it under the ethical rug (on Sundays, I give it a break and enjoy a wee bevvy of single malt Scotch). The devil lies in the details of time, effort, unremunerated cost, and frustration involved with trying to notify patients of significant re-interpretations of test results or the availability of new testing technologies. A recent systematic review of DTR by Ellen Otten and her Netherlandish colleagues concluded that, broadly speaking, patients value being recontacted whereas clinicians feel that DTR is desirable but impractical.

I was surprised to learn that the American College of Medical Genetics is the only professional organization that has issued a formal statement in support of DTR, initially in 1999, with an update in 2013 specifically addressing clinical exome sequencing and clinical genome sequencing (Readers, please let me know if I am mistaken). I am not aware of case-law or legislation that mandates DTR, but I would feel awfully uncomfortable if a law suit were brought against me for failure to recontact a patient. It is hard to ignore something that carries the label “duty.”

In a previous posting I suggested that  labs should refrain from reporting variants of unknown significance (VUS) because VUS should virtually never be used to guide clinical practice, and that labs should track VUS and alert clinicians to significant reclassifications. That blogpost generated interesting discussion on all sides of the issue. Collaborative databases such as ClinVar and PROMPT may help sort out the clinical relevance of human genetic variation, and to some extent relieve individual labs of part of the burden of dealing with VUS. But these efforts will only further the importance of clear and reasonable DTR guidelines. We are in this to improve the lives of our patients, and if advances in genetic knowledge are not used to help clinical care, then we have a  failure on our hands.

As a first step, let me offer some suggestions toward establishing reasonable DTR guidelines:

  1. The primary – but not exclusive – responsibility of monitoring and reclassifying variants should lie with the original testing laboratory or whichever corporate entity might one day buy out the lab.  However, transparent sharing and curating of data among labs – such as with PROMPT and ClinVar – is critical and should be supported by government funding and built into the cost of testing. Classifying variants is enormously complex and the final word requires more than just a few smart people at a single lab rendering their opinions.VUS scale
  2. Labs should make good faith efforts to contact ordering clinicians – not patients – when a variant is reclassified. The clinician is responsible for integrating the test results into patient care. If the clinician is not reachable or no longer affiliated with the same institution or practice, then the original ordering facility should be notified. If efforts to re-contact clinical personnel fail, labs might then consider contacting patients directly, though this could be left up to individual lab policy. If all attempts to recontact fail, well so be it, but should be fully documented. If clinicians do not want to take on the responsibility of DTR, then, quite frankly, they should not engage in the practice of ordering genetic testing and should refer their patients to geneticists or other clinicians who are willing to assume this task.
  3. DTR should be limited to situations where the reclassification of a VUS has direct clinical impact. Thus, there should be no DTR if a VUS is “down-graded” to a polymorphism or a benign allele. In my experience, the vast majority of VUS are down-graded. Alerting patients to every variant and then notifying them months or years later that the VUS was clinically irrelevant is not the best use of resources and manpower. However, DTR becomes critical if a VUS is “up-graded” to Suspected Pathogenic or Pathogenic, or – the more painful phone call to make – if a Suspected or Pathogenic allele is “down-graded” to a polymorphism (“Uh, that salpingo-oopphorectomy and mastectomy, well, maybe they weren’t so necessary after all.”).
  4. There should a “statute of limitations” on how many years out from the testing date that DTR would apply. My daughter suggested 7 years from the time of the original interpretation; she tells me that this is consistent with the length of time that care providers are legally required to keep patient records. I might be persuaded in favor of five years, in light of the mobility of clinicians and patients, the inevitable business cycle of lab acquisitions/mergers/closures, and advances in genetic testing that will rapidly make today’s cutting edge techniques look as elegantly primitive as Clovis point technology.

    iClovis

    iClovis

  5. When undergoing genetic testing, patients should fill out a form with their contact information. Patients should be actively involved in their medical care and this brings with it an obligation for patients to inform clinicians of contact information, along with details of who and how to contact if the patient becomes deceased, mentally incompetent, or otherwise unreachable.  Ideally clinics would contact patients every two years or so to update contact information. While this is theoretically straight-forward with electronic medical records (EMR), most EMR are far less flexible and surprisingly less able to allow such seemingly straight-forward database functions. Getting your IS department to extract individualized reports, mail merges, and data analysis from the EMR is almost as difficult getting the US Congress to pass meaningful legislation. And, to add another layer to participation in their own care, patients should be permitted viewing access to online VUS databases, which should be made user-friendly. It may not be what every patient wants, but it should be available for those who wish to pursue it. In this area, we could learn a lot from direct to consumer genetic testing labs, which are light years ahead of us in designing easy to use, highly informative, up to date websites and creating on-line communities.

Some of you will support a few of these proposals and think that others are about as good an idea as Discount Colonoscopy. But if we don’t do something then nothing will ever get done. What are your thoughts?

 

Once again, thanks to Emily Singh for doing the hard work on the graphics (really, isn’t iClovis très cool?).

 

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by | October 13, 2014 · 11:12 PM

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.

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