Tag Archives: gene panels

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


Genetic testing for single disorders is rapidly going the way of yogh (Ȝ), eth (ð), and thorn *(Þ), those Old English fossil letters of the alphabet. With the advent of massively parallel sequencing and other new testing technologies, multi-gene panels are the wave of the immediate future. Some labs offer testing for 1700 genetic diseases on a single saliva sample. Single gene tests will soon seem as quaintly ancient as The Canterbury Tales.

The eye-blink rapidity of the evolution of genetic testing has made this an exciting time to be a genetic counselor. There is much to be said about multi-gene panels and the technological, scientific, clinical, ethical, and social issues that they raise. Here I want to share a recent experience with a hereditary cancer risk gene panel that made me think about some less discussed issues stemming from gene panels – Will patients  be able to understand this Midas-like wealth of genetic information, integrate it into their health care, and share it with their families? How adequate are current counseling strategies to deal with this complexity? 

My bright and educated patient had been diagnosed with young onset breast cancer, as had several of her first degree relatives.** One of these relatives previously had normal BRCA analysis. No other relatives had been diagnosed with cancer. A multi-gene panel indicated that my patient carried two pathogenic mutations, one in BRCA1 and the other in MUTYH. On the surface, this is not too complicated – a dominant mutation (BRCA) and a recessive condition (MUTYH polyposis) within one sibship, something that a first year genetic counseling student would be able to think through without much difficulty.

Simple. Or so it seemed until the discussion quickly became complex when I started switching back and forth between dominant and recessive inheritance and the different risks to siblings, nieces, and nephews; the need to test the patient’s spouse and potentially her siblings’ spouses for MUTYH mutations; and what further hereditary breast cancer genetic testing might be worth considering for the affected sibling who previously had normal BRCA analysis. It was like trying to focus on two different radio stations that were playing different songs simultaneously.

When a test result indicates a pathogenic mutation, I provide a detailed letter to the patient that serves as a guide to clinical management and to review the implications for the patient’s family. My first go-round with writing the letter for this double mutation patient was a 7 page affair that left my head aching. I eventually settled for two 3+ pages letters, one for each condition, but it still felt unsatisfactory to me. The follow-up took several sessions, a large chunk of administrative time, and multiple phone calls. Because some relatives do not live in the immediate area, it will be difficult to know how well this information will be communicated to the rest of the family.

Think of those female family members who may wind up testing positive for the BRCA1 mutation and carrying two MUTYH mutations. Will they have the drive to undergo annual colonoscopy, annual mammography, annual MRI, monthly self-breast exams, semi-annual physical breast exams, and whatever other screening we might suggest? Or elect to have risk-reducing salpingo-oophorectomy, prophylactic mastectomy, and, if they have a high polyp burden, prophylactic colectomy? That is asking a lot of someone, to say the least. Many patients will follow screening recommendations initially but after five or so years may begin to fall off in their compliance if the demands are too great.

And that is just for a small gene panel. No doubt we will encounter multiplex mutation patients who carry more than just two high risk genetic markers as routine whole genome/exome sequencing comes closer to reality. We cannot expect patients to regularly consult their genomes on a daily or weekly basis, like a genetic I Ching, to guide their life choices.  I suspect what may happen is that patients will focus on a few aspects of one or two diseases depending on their particular circumstances and experiences, and let the rest fall by the wayside. I not uncommonly encounter BRCA positive patients who say “Well I don’t have to worry about ovarian cancer because there is only breast cancer in my family, so there is no need for me to have my ovaries removed.” Even for the most medically sophisticated, highly motivated, and well-educated patients, there is a limit to how much information they can process and act on.

Then there are the possible psychosocial implications and narcissistic threats engendered by carrying not just one but multiple gene mutations, and the familial issues as increasingly complicated information is transmitted across the kinship network. With no family history of colon cancer, the MUTYH results came out of the blue and added another level of psychological complexity by raising concerns about a cancer that had not been part of the family’s prior medical landscape.

Some labs provide excellent educational materials, far better than what most counselors can put together with their limited time and resources. However, these pamphlets and online materials are geared toward explaining a single disorder within a family, not with providing a comprehensive narrative that interweaves the implications of multiple hereditary conditions. We need to develop  better counseling and education techniques to allow patients to effectively utilize complex genetic information and to help patients adhere to a screening strategy with as few financial, practical, scheduling, and emotional barriers as possible. Genetic testing may become relatively inexpensive and widely available, but the social and ancillary medical costs may be where the real expense lies . And that is not even considering the massive problem of maintaining properly curated databases to track, study, and communicate information about variants of uncertain significance.

To some extent, the situation may be analogous to PKU. As thoughtfully discussed in The PKU Paradox by Diane Paul and Jeffrey Brosco, PKU is typically described as a straight-forward mendelian recessive disease that has a remarkably effective simple intervention. PKU has had its share of astonishing success that has provided moral capital for justifying all kinds of genetic testing. Hundreds of millions of babies have been screened for PKU.  However the clinical, ethical, resource utilization, and social issues engendered by PKU screening are anything but simple, far from being resolved, and we are still uncomfortable acknowledging them. And that is for just one relatively uncommon genetic disease. Those problems will be magnified as we test for many conditions, some of which are not so rare.

PKU Cover

Am I sounding an alarm over a non-issue? What are the thoughts  and ideas of our DNA Ex readers?

* – A little bit of language trivia for the curious reader: The letter thorn (Þ), which represents the phoneme “th” (/θ/) as in “there,” survives in modern English in a peculiar role in the names of certain businesses like Ye Olde Clothing Shoppe or Ye Dragon’s Den. The Y in “Ye” is derived from the Early Modern English version of thorn, which was indistinguishable from the letter Y. “Ye” in these names is a modern cutesy way of spelling “The” and “Ye” should be properly pronounced “the” rather than “yee.”

**- Clinical details have been changed to maintain confidentiality.


Filed under Robert Resta

Questions For The Panel

If you are a genetic counselor engaged in testing for hereditary cancers, I suspect you are as bewildered as I am these days. With so many labs offering BRCA testing post Association for Molecular Pathology v. Myriad Genetics, Inc. it is difficult to know which labs best serve our patients in terms of value, reliability, insurance coverage services, clinical support, and quality assurance. Familiar labs are offering new tests and unfamiliar labs are offering testing at Costco prices. Not to mention various law suits and counter-suits over BRCA testing that make me worry that some judge somewhere is going to tell a lab to put all of its testing on hold, leaving patients’ test results in legal limbo.

But what really has me confused – and not a little bit upset – are the new multi-gene cancer panels.

The advantages of the multi-gene panels are obvious. They are cost-effective. They help avoid pondering “Gee, that family really could have been a Cowden. I really should have run PTEN” into the sleep-disturbed wee hours of the morning. Panels will also probably result in significant syndromology reassessment. If you offer PTEN testing only to families who look like they  have Cowden syndrome,  you lose much of the true clinical variability of the condition. And, with all respect and apologies to Robb Pilarski,  Cowden syndrome is in serious need of re-assessment.

Savvy patients are beginning to demand multi-gene panels because they read about them on the Internet or heard about it at their support groups. And I would not be at all surprised if DTC marketing of gene panels starts to rear its ugly head along side the tadalafil, cyclosporine, ibandronate, and eszopiclone commercials that run during the evening news.

So what’s not to like about  multi-gene panels? Let’s face it – many of us are just plain bored with BRCA testing. Panels all cost about the same price, and not terribly more expensive than just running BRCA1/2. Woe to a clinic that only offers BRCA1/2 testing when their crosstown rival routinely offers multi-gene panels to everyone. And who wants to look like an out-of-it fuddy dud who only offers a test developed in the previous century? Isn’t it great to have a choice to run a 6 gene panel, a 16 gene panel, a 26 gene panel, or a 49 gene panel to suit the needs of patients and clinicians? You just choose the panel that’s right for the patient.

And therein lies the rub. How do I know which panel is right for my patient? Labs offer little in the way of clarification as to why certain genes are included or excluded from a panel. From the clinician’s perspective, it seems like the choices reflect the arbitrary expertise of the lab with certain genes, the economic calculations of a given lab, and the desire to out-gun the other labs – why sail a 6 gun sloop when a 40 gun ship of the line can blow it out of the water? In my darker moments, I think that we sometimes choose a lab because a famous geneticist is affiliated with it or a friend from grad school works there.

If clinicians and the labs are honest about it, most of us have little idea of how to guide patients who have a deleterious mutation in genes like RAD51, GEN1, XRCC2. Sure, most labs provide references that might justify inclusion in the panel. But the labs do not cite contrary articles that suggest the predictive power of the particular gene might be low nor do they mention the paucity of publications on the clinical management implications of many of the genes.

There is also a noticeable absence of information on the demographic, clinical, or family history characteristics that might point to one panel over another. Are mutations in one set of genes more common in Russians, Japanese, or Native Americans? Are weak family histories suggestive of one group of genes and strong family histories indicative of another set of genes? What about age of onset? The tumor’s genetic or pathologic profile? Breast only families? Breast and colon families? Clinicians don’t know and neither do the labs.

A step in the right direction will be the pre-conference symposium on gene panels at the upcoming NSGC Annual Education Conference on October 9th. But that is only small bandage on a gushing artery. Bigger measures are needed, and here I offer a few:

1) The key professional organizations – NSGC, ASCO, SGO, etc. – need to form a joint committee that identifies a minimum set of critical genes that should be included on all breast, ovarian, or whatever cancer panels, à la newborn screening. Labs would be free to include whatever additional tests they would like. A joint panel would prevent each society from recommending its own preferred panel that might result in confusingly different recommendations from other professional organizations. Such a panel must take great pains to avoid any financial or intellectual biases.

2) The genes included on the panels should be rated according to their clinical utility and the strength of the data based on an analysis of peer-reviewed publications.

3) Centralized databases should be established for tracking patient outcomes,  clinical and demographic variables, and variants of uncertain significance. Labs that fail to participate in joint databases should be singled out so that clinicians would have the option not to utilize labs that declined to participate in joint registries. While it is important for labs to stay competitive, fiscally sound, and profitable, we can’t lose sight of the core ethical value that the primary goal of genetic testing is to serve patients, not bottom lines. Failure to share data strangles the tree of patient care at its roots.

4) Lab websites should include a balanced discussion of the pros and cons of why each gene is included in the panel – particularly for those genes that are not recommended by the above suggested joint committee – and a regularly updated link to a Pubmed search for that particular gene, not a simple link to one or two articles.

5) The joint committee could also serve an advisory and educational role to health insurers so that patients have equal access to appropriate testing, regardless of which plans cover them.

No doubt The DNA Exchange’s wise and insightful readership have their own ideas, opinions, and recommendations. Let’s hear about them.


Filed under Robert Resta