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According to study findings presented at the American Society of Human Genetics (ASHG) 2019 Annual Meeting, health reports from direct-to-consumer (DTC) genetic tests that adopt a limited variant screening approach are producing clinically false-negative results.



The advances in next-generation sequencing (NGS) technologies that have occurred since the "Genomic Era" mean that DTC genetic testing is now increasingly affordable – and more of us are opting to do it. These genetic tests are marketed directly to consumers via an array of advertising platforms, print, television, or the internet; and the tests can be purchased online or in shopping stores. A customer purchases the test, sends the company a DNA sample and receives their results directly – there is no intervention from a healthcare provider. DTC companies offer genetic tests for an array of purposes, be it to make predictions about an individual's health, to provide information on common genetic traits, or to offer insight on an individual's ancestry.



The popularity of DTC genetic testing has grown to the extent that The U.S. Food and Drug Administration (FDA) has authorized marketing of health reports from DTC genetic screens for genetic risk of breast, colorectal and ovarian cancer.



DTC – "It's like reading a book"



Typically, the tests search for variants in a consumer's genome, such as single nucleotide polymorphisms (SNPs), that can increase an individual's susceptibility to disease. However, concern has arisen as to whether the variant screening provided by DTC companies is thorough enough to yield true clinical value.



While limited variant screens may be informative for the variants they detect, they are not designed to detect every variant that has been linked to the disease in question, explained Edward Esplin, MD, of Invitae, who presented the research. "Thus, these health reports may provide a false sense of reassurance and should not be used for making any health decisions without confirmation testing."



Esplin told Technology Networks, "The limited health screens available direct-to-consumer state they should not be used for healthcare decision-making, consistent with FDA recommendations. Clinical tests are designed expressly for healthcare decision-making. Rather than looking at a few variants in a few genes, clinical tests provide comprehensive information on the relevant genes and variants proven to confer increased risk of disease. It’s like proofreading a book. If each gene is a chapter, a clinical test proofreads the entire chapter on that gene, whereas a DTC test may look for errors in only a few letters."



In the presented study, Esplin and colleagues wanted to quantify the clinical false negatives that result from a limited screening strategy. They therefore focused on two FDA-authorized limited variant screening tests, one for MUTYH gene, which detects to variants linked with colorectal cancer, and one for BRCA1 and BRCA2, which identifies three variants associated with breast cancer.



I ask Esplin how we define "limited screening". He tells me, "For tests using limited screening strategies only a small portion of the clinically relevant genetic variants are reported. For example, there are thousands of variants in BRCA1 and BRCA2 that have been shown to increase risk of breast and ovarian cancer in women. Screening tests that provide information on just 2 or 3 of those variants, such as those limited to the 3 BRCA1/2 variants most common in individuals of Ashkenazi Jewish descent, are highly limited. Again, the book analogy is helpful."



The scientists studied 270, 806 patients who had been referred by healthcare professionals for MUTYH genetic testing, and 119, 328 who had been referred for BRCA1/2 genetic testing.



For both tests, they identified that if only the limited variant screenings had been performed, then most patients would have received a clinical false-negative result.



Specifically, for MUTYH genetic testing, 40% of individuals with mutations in both of their MUTYH genes (which is consistent with 100% lifetime risk of developing colorectal cancer) would have been missed. 22% of carriers of one MUTYH mutation, which is consistent with a 2-fold increased risk of colorectal cancer, also would have been missed.



When analyzing BRCA1/2 the variants tested were significantly more common amongst Ashkenazi Jewish study participants. However, even among these individuals, 19% would have received a false-negative result, and 94% of non-Ashkenazi Jewish individuals carried a BRCA1/2 mutation that would have been completely missed.



Esplin tells me, "Our study did not evaluate the reasons behind the variation in these populations that we observed. This is an important area for further study. That said, it stands to reason that if a test is looking at just 2 or 3 variants associated with a specific population, such those of Ashkenzai Jewish descent, populations likely to have substantially less of that heritage will exhibit substantially fewer of those variants."



He continues, "A clinical false-negative result can be incorrectly reassuring, excluding a patient from receiving the preventive care they need based on their risk. It could be the difference between preventing cancer and developing cancer."



Analyzing differences among populations



Esplin's team analyzed the rate of false-negatives among patients of different ethnic backgrounds. Their results show that for MUTYH, 100% of Asians, 75% of African-Americans, 46% of Hispanics and 33% of Caucasians would have received a clinical false-negative. In parallel, for BRCA1/2, 98% of Asians, 99% of African-Americans, 94% of Hispanics, and 94% of Caucasians would have also received a clinical false-negative.



Collectively, these findings emphasize the medical worth of conducting in-depth, comprehensive clinical genetic testing. "The results from this type of DTC genetic screening may not be wrong but they are woefully incomplete, particularly when viewed against the health question a patient may be asking - am I at risk for cancer. We hope our research underscores the need for consumers to understand the deep limitations of these health reports and seek out appropriate clinical genetic testing when trying to understand their risk of health conditions like cancer," says Esplin.



I ask Esplin what his advice would be to individuals considering a DTC genetic test. He tells me: "Think about the question you hope to answer by taking the test. If you are interested in whether you are at risk for a disease, you need a comprehensive, medical grade genetic test that can answer that question and be used by you and your physician to take action on the result. So if you want to know if you’re at risk for cancer, you need a comprehensive clinical genetic test that evaluates all of the gene changes that can increase your risk. It is easier than ever before to get the tests genetic experts trust thanks to offerings like ours that link patients to clinicians via telemedicine. If you’re interested in getting a health answer, get a medical test."



Reference: ED Esplin et al. (2019 Oct 17). Abstract: Limitations of direct-to-consumer genetic screening for hereditary breast, ovarian, and colorectal cancer risk. Presented at the American Society of Human Genetics 2019 Annual Meeting. Houston, Texas.



Edward Esplin, M.D., was speaking with Molly Campbell, Science Writer, Technology Networks