Masking The Truth?

A recent hereditary cancer multigene panel result got me to thinking again about the thorny problem of incidental findings in genetic testing. My goal here is not to criticize the lab, whose staff was very helpful and open in our discussions, but rather to encourage open debate about the scope of results that clinicians want from genetic testing and how this jibes with patients’ expectations. Our expectations might be quite different from what patients want, and this plays an important part at the end of this story.

My patient was recently diagnosed with breast cancer, and had a family history of breast cancer. One relative with breast cancer had already undergone BRCA testing, with normal results. The family history was non-specific but contained a hodge-podge of cancers that gets you to scratching your head – breast cancer, a primary brain cancer, a non-smoking relative who died before 50 of lung cancer, an aunt who died of some type of gynecologic cancer, and a few other malignant odds and ends. Given her relative’s normal BRCA results, we agreed that she would be best served by multigene panel testing, after a discussion of its potential downsides.

Like 87% of my patients, no cancer-linked pathogenic mutations were identified. However a pathogenic EPCAM point mutation caught me by surprise.

For those not familiar with the genetic architecture of Lynch syndrome, five genes are linked to Lynch syndrome – MLHL1, MSH2, PMS2, MSH6, and EPCAM. The underlying mutational basis is different for EPCAM than for the other 4 Lynch genes. EPCAM is MSH2’s upstream neighbor. Mutations in EPCAM itself do not directly cause Lynch syndrome. Instead, large gene deletions in the distal part of EPCAM result in loss of its poly A tail that should signal the end of the coding region. RNA transcription does not stop, leading to an EPCAM/MSH2 chimera of a transcript. By a mechanism not fully understood, this results in hypermethylation of the MSH2 promoter and absent/reduced expression of the  MSH2 gene product. EPCAM deletions constitute a small but significant minority of Lynch syndrome gene mutations and so labs routinely analyze EPCAM for large deletions.


So why was the lab reporting a point mutation in EPCAM? My first (insecure) reaction was “Well, I guess point mutations in EPCAM cause Lynch syndrome. Just another in the steady stream of new genetic findings that flew under my radar but that everybody else seems to know.” I breathed a small sigh of relief and a temporary break from my professional insecurity when further reading of the report confirmed my understanding that point mutations indeed do not produce Lynch syndrome.

Autosomal recessive EPCAM point mutations are linked to congenital tufting enteropathy (CTE), an uncommon disorder characterized by diarrhea so profound that patients often require ongoing total parenteral nutrition. Clearly my patient did not have CTE nor did any of her children, who were all well past the age when CTE would have manifested. The issue here, as any genetic counselor will tell you, is for the health of her grandchildren. Each of her children has a 50% chance of having inherited the EPCAM mutation. If a child has inherited the EPCAM point mutation and if the child’s spouse is also an EPCAM point mutation carrier, then my patient’s grandchildren from this mating would have a 25% chance of having CTE. Essentially my patient’s multigene panel test was transformed into a carrier screening test for a metabolic disorder for the next generation (The punster demon in me who I cannot control just remarked “Her grandchildren’s risk? Now that’s real NextGen sequencing! Or maybe NextNextGen.”).

Godfrey Hardy

Wilhelm Wienberg

Wilhelm Wienberg

But, statistically speaking at least, the patient should not worry too much about her grandchildren. The frequency of CTE is between 1/50,000 and 1/100,000, which hardyweinbergs out to a carrier rate of about 1/135. Thus, the likelihood that my patient would have a grandchild affected with CTE is 1/2 (the chance that her child would be a carrier) x 1/135 (the chance that her child’s spouse would be a carrier) x 1/4 (the chance that the grandchild would inherit two mutated EPCAM alleles) = 1/1080. Using the time-honored genetic counselor’s trick of reframing, there is a 99.9% chance that my patient’s grandchild will NOT be affected with CTE. Did my patient really need to know this in the midst of her cancer treatment?

I recognize that some patients undergoing multigene panels are still in their reproductive years and this information could be important to them. And one could argue that this situation is no different from other genes included on multigene panels that are also associated with different disorders when they occur recessively – NBN, BRCA2, ATM, fumarate hydratase. But I would counter that those other recessive disorders are qualitatively different situations. The same type of mutations that predispose towards cancer when they occur in the heterozygous state also predispose towards ataxia telangiectasia and the other recessive conditions and so one cannot avoid knowing that the patients carries the mutation. However, EPCAM point mutations are not linked to cancer and thus are not relevant to the reason why the test was performed to begin with. The lab included the EPCAM point mutation because of the nature of their testing platform, which can’t help but detect EPCAM point mutations.

But should the lab have masked the results? Labs mask all kinds of genetic test results, hence the list of incidental findings that the American College of Medical Genetics recommends be reported to patients undergoing whole exome/genome sequencing even if they were not seeking that specific information (CTE is not on that list, though of course this patient did not have whole exome/genome sequencing). From a counseling standpoint, it might be an undue burden on patients to layer on a whole other level of psychosocial concern when they come to us primarily concerned about their cancer risks or treatment options and are not even thinking about their descendants’ risks of having rare genetic diseases. Another downside to reporting EPCAM point mutations is that it increases the frequency of finding variants of uncertain significance (VUS), the problem child of multigene testing. As fate would have it, a few days later another patient’s test revealed an EPCAM VUS.

So after stewing on this and discussing it with colleagues, I was considering asking the lab to mask EPCAM point mutations in the future. But then I met with the patient to review the results. Not only was she not upset, she was excited and grateful about learning the information. She said that she underwent the testing to learn what risks her family faced, and as far as she was concerned, the CTE risk fit into her expectations even though I had never discussed it with her beforehand. Nor is she apparently an outlier. At this year’s ASHG conference, researchers from the Kaiser Permanente Northwest Center for Health Research discussed the results of an ongoing study in which 320 non-pregnant women have been randomized into two groups that underwent carrier testing. 200 women received usual care and 120 women underwent genome sequencing for 750 carrier conditions and ~100 secondary findings. Women in the genome sequencing arm were required to receive results about life-span limiting conditions but could elect to receive results of all or some of five broad categories of findings (serious outcomes, mild outcomes, unpredictable outcomes, adult onset diseases, and medically actionable secondary findings). To date, 90% of those in the intervention arm have elected to receive results in all categories. Patients can’t seem to get enough genetic testing.

Maybe this enthusiasm stems from the excitement and sexiness of undergoing genetic testing, which for most people is a new thing and so there is still lots of gene spirit. Or maybe patients just don’t know enough to not want extensive genetic testing and eventually reality will set in when enough people undergo genetic testing and patients may become more reluctant to learn tons of questionably useful information (although the experience of 23andMe suggests otherwise). Maybe that day will come. But for now, whether genetic counselors like it or not, many – though by no means all – patients want to know a lot about their genetic make-up and want a choice in what they can know, even if it is not of immediate clinical value. The clinical utility of a test does not necessarily equal its emotional utility.

Cost is no longer a factor; until recently, genetic testing would include the minimal number of genes because of the expenses involved. Nowadays, however, it essentially is no more expensive to run 5 genetic tests on a sample than 500 genetic tests. Patients and their families are the primary stakeholders so patient demand and expectations should be an important factor in determining the shape of genetic testing, though genetic counselors should offer guidance through our wisdom and experience.

We also need to include all concerned parties in this discussion, such as the disability community and other patient groups affected by genetic diseases. And we need to serve as a counter-balance to some of the “Rah-Rah Ain’t genetic testing grand” advertising of some genetic testing labs. This will require open minds, finely honed counseling skills, and the development of new educational resources that will help patients better understand the bewildering array of genetic diseases and the strengths and limitations of genetic testing. At the end of the day, genetic counseling is still primarily a psychological encounter between two human beings. Here is where the future of genetic counseling lies.


Filed under Robert Resta

13 responses to “Masking The Truth?

  1. Ilana Lowy

    Bob, I’m curious to see if such enthusiasm for genetic knowlege and for screening, seen e.g., , in screening for cancer, exists elsewhere too; My guess is that not, and that this a particularity of the US (like say, baseball or love of firearms) ; but I may be wrong.

  2. Robert Resta

    Ilana – I don’t think that the desire for genetic information is limited to cancer patients. In addition to the study I mention in the blog post on healthy patients undergo preconception carrier screening, here are a few other examples of studies that have found that, at least in the US, patients want as much genetic information as possible even if it is not clinically actionable:
    1) .M. Bollinger, R.C. Green, D. Kaufman
    Attitudes about regulation among direct-to-consumer genetic testing customers. Genet. Test. Mol. Biomark., 17 (5) (2013), pp. 424–428
    2) A. Harris, S.E. Kelly, S. Wyatt
    Counseling customers: emerging roles for genetic counselors in the direct-to-consumer genetic testing market. J. Genet. Couns., 22 (2) (2013), pp. 277–288
    3) Am J Med Genet A. 2014 Feb;164A(2):ix-x. doi: 10.1002/ajmg.a.36418.
    Patients and families generally welcome secondary genomic findings: support for return of incidental findings may encourage shift toward predictive genetic testing. Levenson D.

    Probably patient expectations will vary with age, cultural background, out of pocket costs. However, for now, I think that on average in the US patients want more genetic information than less. This might be a US specific phenomenon; it is worth investigating.

    • Abby Lippman

      When you investigate, take into account (among many other things) the role of DTCA in the USA. (Ditto class issues where there is no public insurance.) DTCA is not as pervasive elsewhere, and could(along with privilege) be playing a bit of a role in the enthusiasm for testing???
      Thanks for another thoughtful commentary, Rob.
      abby (lippman)

    • Ilana Lowy

      Bob, many thanks for the references, and for the excelent text. II did not want to say that only cancer patients want to have more information — I just learned from Eric Vilain that people treated for DSD in the US also want to know ‘everything’ about their genome. I’m just more familiar with the the wish to have all the available infromation in the US , which was described in the context of cancer screening (e.g. Lisa Schwartz et al ‘Enthusiasm for cancer screening in the US’. JAMA, 2004, 291(1): 71-78). Lisa also thinks that in the UK people are much less keen to ‘know all’.

  3. excellent article. 10/10.
    and to contribute the discussion above: in my emerging experience in Uruguay (South America) the patient´s interest in their own genetic information (depending on cultural background, of course) is similar, as well as the desire to have proffesionals which whom they may discuss it.

  4. Shannon

    I love you thought provoking posts! I would like to challenge the comment that “cost is no longer a factor”. I think this argument only works if the patient is paying 100% for their own testing and they have the funds to pay for it. Do you think that having commercial or government insurance to cover the cost of testing that has little clinical utility but has emotional utility is an appropriate use of healthcare dollars? I hear this argument a lot when labs say…well the patient only pays X dollars. This is true but “someone” pays for it, and many times in the end it is still the patient through increased premiums or decreased benefits. Dressing up expansive genetic testing as medically necessary when in reality the testing comes down to the “patient wants it” is irresponsible. I would also challenge genetic counselors think about times when there shouldn’t even be the expectation that any form of insurance should cover genetic testing. There is a role for DTC genetic testing or even genetic testing through a healthcare provider without the expectation of insurance coverage.

  5. megweg79

    I have to agree that my experience in pediatrics has been most patients (not all) want more, not less. They are happy to hear information that may not be specifically related to the indication for testing/diagnosis. Then again, the patients that are seeking further testing (beyond the basics – exome, multigene panels etc) are clearly the “information seeking” type.

  6. Kathleen Berentsen


    Thanks for the great write up. To add to the reference list above (and you may have highlighted this in the other post you mention) but it’s worth mentioning again as Dr. Lindor presented on this at the CGA conference today:

    Public perceptions of disease severity but not actionability correlate with interest in receiving genomic results: nonalignment with current trends in practice.
    Graves KD1, Sinicrope PS, McCormick JB, Zhou Y, Vadaparampil ST, Lindor NM.

    “Conclusions: The respondents from the general population were confident in making their own decisions. The responses suggested different priorities than current expert-driven approaches. The emphasis on binning genes may be missing a complementary, simplifying approach of grouping patients based upon their all/none interest in genomic results. This study illuminates important differences between the general public and genetic experts.”

  7. Pat Himes

    Thanks, Bob! As one of the genetic counselors on the NextGen study, I have been amazed at the enthusiasm with which our study participants approach genetic testing. “knowledge is power” is a recurrent theme. It will be very interesting to learn (as we hope to do so) if they feel the same way several years out. We will continue to share the results, so keep posted. We will be coming out with a paper describing why people decide against participating in the study, hopefully in a few months. Can’t wait to read your analysis and whatever puns you will generate!

  8. Robert Resta

    What a bunch of great comments.

    Abby and Ilana – I think the centralized health care insurance in Canada and the UK will have some damping influence on patient enthusiasm for genetic testing. But now that 23andMe’s SNP disease risk testing is available in Canada and the UK, we may get something of a barometer of public enthusiasm for genetic testing in those two countries, assuming that 23andMe makes public its sales in those countries.

    Victor – very interesting to hear from Uruguay. Keep us posted on how this plays out in your country.

    Shannon – good points about who should pay for what. But think of this – if patients qualify for insurance coverage for, say, a multigene cancer risk panel, it does not necessarily cost any more to add on other tests to the panel. So, at least in those cases, no more money is being spent for the extra information.But this begs the question of what follow up screening, surgery, etc. should insurers cover if the “extraneous” genetic information shows an increased risk of developing some disease.

    Kathleen – thanks for bringing Dr. Lindor’s study to my attention. I think her data rings true and echoes the day to day clinical experience that commenter megweg79 and other genetic counselors relate to me. Perhaps we are guilty of the sin of paternalism (and megweg79, you should change that to your legal name. Sounds like a name for a way hip DJ on some fringe radio station that only plays interesting music by bands that no one ever heard of, like KEXP here in Seattle).

    Pat – look forward to hearing more ongoing results from the Oregon study. I have no control over the puns, though; they just well up spontaneously and unpredictably from some dark corner of my brain as I watch in helpless horror. Clearly I have a nonsense mutation in some critical language gene (Oh, God, there it goes again….).

  9. Beth Sheidley

    I wonder how that EPCAM point mutation would have been interpreted/explained to the patient if the provider had not been familiar with genetics? 😉

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