Frequently Asked Questions (FAQs) 2017-07-27T10:18:33+00:00

FREQUENTLY ASKED QUESTIONS (FAQs)

Why does CGI’s Variant FactChecker™ research-use-only variant classification sometimes disagree with the classification from the originating laboratory? 2017-09-12T15:20:38+00:00

Sometimes CGI may not have access to all of the information that the originating laboratory has to include in its CGI’s Variant FactChecker™. Most often disagreement occurs because laboratories and companies frequently use different variant classification protocols to assess the same publicly available evidence. CGI’s assessment protocol is stricter than the ACMG recommended minimal classification standards used by the many USA and international laboratories. CGI’s variant classification method is designed to better minimize false positives compared to most methods. However, in some situations, less stringent approaches to variant classification may be clinically advisable. A qualified healthcare professional can help the patient judge the associated risks and benefits.

Can I use CGI’s Variant FactChecker™ research-use-only variant classification to guide or influence my clinical care? 2018-04-18T20:45:07+00:00

CGI’s Variant FactChecker™ is not intended to alter clinical management. It is a research-use-only report provided by CGI for patient and clinician research and is not for clinical use. The classification or reclassification of a variant issued by the genetic test originating laboratory/company, in connection with other clinical inputs and the clinician’s professional judgment, should inform clinical care. The responsibility and liability for accurate clinical variant classification remain with the originating laboratory/company performing the genetic assay and the entity that issues the genetic test report.

 

For CGI’s Variant FactChecker™, does CGI evaluate all the publicly available evidence for my variant? 2017-09-12T15:20:17+00:00

CGI endeavors to evaluate all the publicly available evidence for a variant. CGI uses a strict variant classification protocol which triages out evidence which CGI determines is of weak or no clinical value for variant classification. CGI’s Variant FactChecker™ report summarizes all of the evidence CGI used to arrive at its research-use-only classification.

For CGI’s Variant FactChecker™, will CGI talk to the originating laboratory/company that issued my original report? 2017-09-12T15:20:07+00:00

If a patient has questions or concerns about CGI’s Variant FactChecker™ findings compared to the findings in their original report, the patient and their healthcare provider may share CGI’s Variant FactChecker™ with the originating laboratory. CGI welcomes follow-up discussion with the originating laboratory’s scientists. Discussion may lead to a re-assessment of evidence or the sharing of additional evidence. Sometimes this will result in either or both the laboratory or CGI issuing an amended report. In such situations, if CGI reassesses and makes a meaningful update to its evaluation of the variant, CGI intends to issue the patient an amended Variant FactChecker™ report within two calendar months of first issuance, at no additional cost to the patient.

Can I order Variant FactChecker™ for my tumor (somatic) genetic test? 2017-09-12T15:33:00+00:00

At this time, Variant FactChecker™  is only for patients who have received hereditary disease testing. This is the testing done for diseases that run in the family or that strike young children. While Variant FactChecker™ is well suited for hereditary cancers, it is not currently offered for somatic genetic tests on patient tumor sample. Contact CGI if you are interested in Variant FactChecker™ but are unsure of the type of genetic test you received.

Which healthcare professionals understand CGI’s Variant FactChecker™ technical details? 2017-09-07T16:49:25+00:00

If complex genetic case assessments are outside the scope of a patient’s current healthcare provider, CGI recommends that the patient seek out a Medical Geneticist or a Certified Genetic Counselor. Within the USA, insurance sponsored provider lists and the NSGC website are useful resources.

How common are hereditary diseases? 2017-09-07T16:48:23+00:00

About 8% of Americans are affected by a rare genetic disease. The percentage is roughly the same in European countries. There are many different kinds of genetic diseases with varying levels of severity. Some ancestral populations have a higher prevalence of certain genetic disease(s) than others. Our Hereditary Diseases page lists many of the genetic diseases.

What is genetic testing? 2017-09-07T16:49:01+00:00

The purpose of genetic testing is to discover differences in a person’s DNA compared to a human reference sequence. These differences are called variants. Everybody has many genetic variants. Sometimes, one or more genetic variants in a person may lead to abnormality or an increased risk of disease or early death. Different types of genetic testing include diagnostic testing, predictive testing, newborn screening, carrier testing, prenatal testing, preimplantation testing, and tumor testing. For additional information, visit these helpful sites provided by genetic counseling organizations: Genetic Testing hosted by the National Society of Genetic Counselors, and Genetics and You hosted by the Genetic Support Foundation.

How accurate is genetic testing? 2017-09-07T16:47:19+00:00

There are two major aspects to a genetic test’s accuracy within a laboratory or company; the ability to detect a genetic variant (with accuracy often exceeding 98% for DNA sequencing), and the ability to accurately interpret the genetic variant once detected. The latter step of interpretation is the focus of the Center for Genomic Interpretation since in most genetic testing cases interpretation it is the step that is subject to the greatest error. A laboratory or company’s ability to accurately interpret genetic variants differs widely across the genetic testing service industry. In some diseases and genes, and at some labs, accuracy exceeds 99% for interpretation of pathogenic variants (see these publications for Hereditary Breast and Ovarian Cancer and Lynch Syndrome). However, in most other disease states within some labs, the chance of getting a positive result that is inaccurate is much greater than getting a positive result that is accurate. Our Patient Education page contains a useful review of difficulties surrounding accurate variant interpretation and what a patient or clinician can do about it. CGI’s Variant FactChecker service is designed to empower the patient and/or clinician who has received a genetic test result and had questions about its interpretation accuracy.

What is CGI’s mission? 2017-09-07T16:46:48+00:00

The Center for Genomic Interpretation (CGI) saves lives. CGI does this by providing an accurate interpretation of patients and consumers’ genetic variants to help guide clinical decision making. CGI works to rapidly reduce the greater than 50% false positive rate averaged across the clinical genetic testing industry. CGI also works to drive down the indeterminable false negative rate in clinical genetics. Thus, CGI drives quality in clinical genetics. Please visit CGI’s mission page.

What are the benefits for a laboratory or company in partnering with CGI? 2017-09-07T16:46:32+00:00

Visit our Laboratories & Companies page to learn how CGI helps genetic testing companies raise the quality bar while lowering the costs on their genetic variant classifications and reclassifications for customers. CGI’s non-profit business approach proves commitment to our mission to drive quality in clinical genetics by working collaboratively and non-competitively with for-profit companies.

What makes CGI’s approach to variant interpretation more accurate than most other approaches? 2017-09-07T16:46:00+00:00

Our Approach allows CGI to apply the highest stringency methods to variant classification and variant reclassification. CGI questions everything, and demands a higher burden of evidence for variant interpretation than has been traditionally accepted across the industry and by the American College of Medical Genetics and Genomics. CGI drives towards statistical testing and clinical validation of each of its variant classification components. CGI is driven by data, with its co-founders having been instrumental in setting the gold-standards for hereditary and somatic variant classification within the commercial diagnostic industry and US government funded initiatives.

Is CGI a 501(c)(3) non-profit humanitarian organization? 2017-09-19T20:49:46+00:00

The Center for Genomic Interpretation is a registered nonprofit organization. CGI’s IRS 501(c)(3) determination was effective as of April 2017. Please DONATE now and help make a difference.

Can I donate to CGI, and how much can I donate? 2017-09-19T20:48:50+00:00

Yes, you can donate. Donations help CGI accomplish its life-saving mission. Any amount of money can be donated. All donations are appreciated. As a 501(c)(3), you will receive a receipt for tax deduction purposes. Donate here.

Can I get regular email updates about CGI’s progress? 2017-09-07T16:44:39+00:00

Yes, CGI is eager to keep you in the loop. Please click HERE to enter your contact information to receive periodic updates on CGI’s progress.

How can CGI claim that more than half of positives in genetic testing are errors due to inaccurate variant interpretations when averaged across the industry? 2017-09-07T16:44:12+00:00

There are different forms of genetic testing. The genetic testing given to people who seem to have a disease running in their family is most often a DNA sequencing test. While DNA sequencing has been available to many patients for more than three decades, technological advances in the last few years have allowed DNA sequence tests to become routine in many settings. These technological advances have also allowed clinical scientists to begin evaluating the accuracy of previously accepted variant interpretation methods.

In 2014, a large team of scientists published a key article in Nature Genetics exploring whether existing clinical genetic variant interpretations were based on solid evidence. These scientists investigated and corrected variant interpretations in Lynch Syndrome, which is a form of hereditary cancer and is one of the best studied hereditary diseases and has one of the world’s most respected public databases. The scientists independently reviewed the data and collectively downgraded 24% of the positive (pathogenic) classification entries based upon insufficient evidence.

Women with positive Lynch Syndrome variants will often choose to have a hysterectomy and/or remove their ovaries to preempt the high risk of developing deadly tumors, and both men and women will increase their frequency of colonoscopies.  A single false positive variant interpretation often impacts numerous patients but the design of this study did not allow the scientists to evaluate the magnitude of the patient impact due to the unsubstantiated positives that were discovered and corrected by their study.

In a 2016 pre-publication white paper, scientists at  “Human Longevity, Inc.”  asked: If the positive variant interpretations issued by labs and expert committees are to be believed, how many “regular” people from an unselected population would be predicted to be at risk or have a hereditary disease?

They sequenced the DNA and compared the results of these everyday people to the known frequency of genetic diseases in the population using publicly accessible clinical variant classifications (May 2016 ClinVar download). The scientists hypothesized that if the positive classifications within the ClinVar database were all true positives, the frequency of hereditary disease predicted by sequencing the unselected group of people should be no greater than the known frequency of hereditary diseases in the general population (accounting for incomplete penetrance). If the genetically predicted frequency of disease in the unselected group were higher than the known frequency of disease, then the origin of the discrepancy would be false positives from inaccurate variant interpretations found in the clinical ClinVar database.

Human Longevity, Inc. was able to estimate the positive inflation ratio for numerous hereditary diseases due to inaccurate variant interpretation, which they expressed as [observed/expected]. This inflation ratio can be approximated as [(true positive persons + false positive persons) / (true positive persons)] in a tested population. It is important to note that Human Longevity, Inc evaluated only the variant interpretations provided by laboratories who volunteered their classifications into the public ClinVar database.

From their research, positive BRCA1 and BRCA2 hereditary breast and ovarian cancer (HBOC) variants demonstrate false positive rates are of only minor concern once incomplete penetrance is taken into account. However, BRCA1- and BRCA2-related HBOC is one of the most thoroughly studied hereditary diseases. For most other hereditary diseases with defined frequencies in the general population, the false positive rate is astonishingly high, even after accounting for incomplete penetrance.

For example, malignant hyperthermia susceptibility, multiple endocrine neoplasia type 1, Romano-ward long QT and Brugada syndromes, Ehlers-Danlos syndrome (vascular type), Retinoblastoma, and hereditary paraganglioma-pheochromocytoma syndrome all exceed an inflation ratio of 10. Even if we invoke a low 20% penetrance for these so-called positive variants, there is still a greater chance of a person having a false positive than a true positive when receiving a positive genetic test result.

The situation is much worse for rare diseases that primarily impact fetuses, newborns, and children, with inflation ratios exceeding 25x in most rare diseases, and in some cases exceeding an inflation ratio of 1000x. Since these rare diseases may not have very accurate estimates of frequency in the general population, it is possible that the inflation rates may themselves be somewhat overestimated.

CGI has not witnessed significant improvements in the genetic testing industry’s variant interpretations since the 2016 Human Longevity, Inc. study. Therefore, we conclude that for almost all hereditary diseases probed by Human Longevity, Inc., there were much higher odds of a positive genetic test result being false than being true, even when accounting for incomplete penetrance.

We note that Human Longevity, Inc’s study is very recent, and that replication studies will be required to verify or disprove their findings. Thus, CGI tempers its summary of these recent findings and states that more than half of positives are false positives due to inaccurate variant interpretations when averaged across the clinical DNA sequencing industry.

CGI exists to fix the inaccuracies in genetic variant interpretation across the entire industry by requiring a higher burden of evidence for variant interpretations. Until CGI can fix the problem at the source (being the laboratories), CGI offers patients and clinicians the CGI Variant FactChecker™ service, which provides CGI’s research-use-only second opinion service for variants reported by laboratories and companies. Please contact CGI if you believe there is an error in our methodology for this estimate.

How can CGI claim that more than 100,000 families are impacted by false positives in clinical genetics each year in the USA? 2017-09-07T16:43:13+00:00

There are more than 700 laboratories in the USA offering more than 68,000 different genetic tests. (See data collected by Concert Genetics and GeneTests). Our estimate that false positive variant interpretations impact more than 100,000 families in the USA was calculated with the following method and assumptions:

  1. DNA sequencing tests can be divided into two major categories – well-understood gene panels, and less-understood gene panels.
  2. Currently, in the US, there are at least 4,000 patient DNA sequence tests run in well-understood hereditary gene panels per day, and at least 4,000 patient DNA sequence tests run in less-understood hereditary gene panels per day.
  3. There are 260 working days each year in the USA.
  4. There is a 15% positive report rate in well-understood gene panels, and a 10% positive rate in less-understood gene panels for patients with an indication for testing.
  5. The false positive rate in well-understood gene panels is conservatively estimated as one false positive patient result issued for every 19 true positive patient results (inflation of 1.05).
  6. The false positive rate in less-understood gene panels is conservatively estimated as  23 false positive patient results for every two true positive patient results (inflation of 12.5). Please see the FAQ about false positive rates for data from Human Longevity, Inc.

Thus, the number of individuals impacted by false positives in clinical genetics each year in the USA is estimated at 103,480:

260 days x [{(4000 well understood tests/day)x(0.15 positive rate for well-understood gene panels)x(1/20 false positive rate for well-understood gene panels)} + {(4000 less-understood tests/day)x(0.10 positive rate for less-understood gene panels)x(23/25 false positive rate for less-understood gene panels)}] = 103,480 false positive individuals

Please contact CGI if you believe there is an error in our methodology for this estimate.


How does CGI claim that by 2025, erroneous terminations of wanted pregnancies in the US will exceed 16,000 annually due to false positives in variant interpretation unless drastic improvements are made? 2017-09-07T16:43:26+00:00

This number was calculated with the following facts and assumptions:

  1. 4,181,208 births predicted in the USA (all races, all sexes) in 2025.
  2. The American College of Obstetricians and Gynecologists will support prenatal testing for all pregnant mothers for genetic diseases at least as common as Down Syndrome. See here and here
  3. By 2025, the 30 genes currently offered on the Baylor Medical Genetics Laboratories PreSeek test and the Natera Vistara test will be the universally adopted gene set for Non-invasive Prenatal Testing (NIPT). (This is a conservative estimate as many more genes are likely to be added by 2025, which will increase the overall false positive impact from the estimate given here). This gene list is a combination of rare autosomal dominant and X-Linked severe pediatric single gene disorders, with a combined prevalence of 1/600 births, exceeding that of Down Syndrome frequency.
  4. Only 70% of pregnant mothers will have easy access to NIPT. This estimate is based on US insurance coverage for pregnant mothers in the first trimester.
  5. Of pregnant mothers with insurance coverage in the first trimester, we estimate that only 60% of US women will accept NIPT testing. This estimate comes from data which showed 84% of pregnant mothers in the UK who were offered prenatal testing accepted it. Whereas, another study in the USA among Latina women showed a lower acceptance rate of 35%. Acceptance of NIPT in the USA will likely approach that of the UK by 2025. As a conservative estimate, the halfway point of 60% was chosen.
  6. US genetic diagnostic laboratories are currently operating at roughly a 25x inflation of positive variants due to false positives in rare disease genes, as measured by ClinVar submissions of 1+ star rating compared to a large unselected population and disease prevalences in Orphanet, and an assumption of 100% penetrance. However, here we assume a more conservative overall 50% combined penetrance for the disease genes, dropping the inflation rate to 12.5x. See Human Longevity, Inc’s white paper, figure 2B).
  7. False positives will be substantially reduced by trio testing when parental samples and medical histories are provided. NIPT trio testing in 2016 accounted for 29% of NIPT tests in one study for NIPT exome testing (See Baylor Medical Genetics Laboratories reported data).
  8. False positives due to inaccurate variant classification will be repeated on confirmation testing following NIPT, such as amniocentesis or chorionic villus sampling, as the origin of this error is variant interpretation and not sample or analytical error.
  9. While the pregnancy termination rate in Europe of Down Syndrome positives from prenatal testing is 92% (2012 data), the rate is lower in the USA at 67%, (also from 2012 data). For the estimate, the lower 67% rate for voluntary pregnancy termination based on a positive result for NIPT sequencing is assumed.
  10. With the above assumptions, we estimate that by 2025, the number of fetuses in the USA receiving the 30 gene NIPT sequencing test currently on the market per year is expected to be 1,756,107 fetuses. This estimate is calculated as: (4,181,208 births) x [(0.7 pregnant women will have access to non-invasive prenatal testing) x (0.60 pregnant women will accept non-invasive prenatal testing)] = 1,756,107 fetuses get 30 gene test.
  11. The current birth frequency of the genetic diseases associated with the 30 gene test is 1/600 births. Thus, the true positive rate in the fetuses to be tested will be 1,756,107 fetuses x (1/600 genetic disease frequency) = 2927 true positive fetuses.
  12. The inflation due to false positives is expected to be 12.5 when accounting for incomplete disease penetrance. Thus, the number of total positives, including true and potential false positives, will be: 2927 true positive fetuses x (12.5 inflation) = 36,586 true and potential false positives: Thus, the number of potential false positives is: 36,585 true and potential false positives. 2927 true positives = 33,659 potential false positives.
  13. However, CGI hopes that laboratories will continue recommending and supporting quality assurance parental testing to identify likely false positives by identifying variants that are inherited and not de novo, with inherited variants in these specific diseases likely being false positives. Currently, when parental testing is offered in a similar setting, about 29% of cases achieve both parents testing. We assume that up to 29% of false positives will be eliminated in this quality assurance step. Thus, with quality assurance measures in place, the number of false positives will drop to 33,659 potential false positives (0.29 of potential false positives eliminated by parental testing x 33,659 potential false positives) = 23,898 false positives.
  14. As above, In the US, we can expect 67% of genetic disease positive fetuses to be terminated.

 

Thus: (23,898 false positive fetuses) x (0.67 of positive fetuses are terminated) = 16,011 erroneous terminations of wanted pregnancies in the US in 2025 due to inaccurate variant interpretation, unless drastic improvements are made.

Please contact CGI if you believe there is an error in our methodology for this estimate

How does CGI make the claim that more than $1 Billion is wasted annually in the USA on medical expenses associated with false positives in clinical genetics? 2017-09-07T16:42:24+00:00

CGI estimates that greater than 100,000 individuals in the USA currently receive false positives in genetic testing each year due to inaccurate variant interpretation. A variety of downstream medical events follow positive genetic tests results, whether or not the positive is a true or false positive. Additional clinic visits with specialists will almost always follow, and frequently additional and costly procedures or therapies will result. These may include: Orthogonal diagnostic testing, such as MRIs, EKGs, X rays, colonoscopies, muscle biopsies and other invasive scans; Surgeries, such as mastectomies, colectomies, hysterectomies, oophorectomies, medically advised pregnancy terminations and other surgeries; Drug therapies, such as prophylactic chemotherapy, heart medications, seizure and other neurological medications, and many other pharmaceutical interventions. For each positive result we assume that the annual cost in the USA of follow on clinic visits, procedures and therapies is averaged to $10,000 per person total. Thus, 100,000+ persons with false positives originating from inaccurate genetic variant interpretation will cost at least $1 Billion in wasted medical expenses per year in the USA. Please contact CGI if you believe there is an error in our methodology for this estimate.

 

Do interpretation error rates for Down Syndrome and other trisomy genetic tests exceed 50% false positives? 2017-09-07T16:41:57+00:00

No. Down syndrome (trisomy 21), Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13) are genetic diseases resulting from the additional presence of all or a large part of chromosomes. The technologies to accurately detect and interpret these very large genetic changes are not perfect, yet are correct more often than not, with a false positive rate of around 5%. CGI focuses its efforts on interpreting genetic variants that are much smaller than those tested in trisomy testing but may be as severe in their clinical impact. Smaller genetic variants are detected through DNA sequencing technologies. Current inaccuracies in interpreting these type of variants are high, exceeding 50% false positive rate in many diseases at many laboratories.

If more than half of positive clinical genetic test results are inaccurate, why hasn’t regulation or the legal system fixed the problem? 2017-09-11T15:49:19+00:00

Please visit our Patient Education page to learn more about the focus of regulation in genetics. In short, the accuracy of variant interpretation is poorly regulated, which likely results from the fact that variant interpretation accuracy could not be estimated in any meaningful way until recently. The USA legal system has not yet had a significant impact on improving variant interpretation accuracy industry wide. Until very recently, the problem of unsubstantiated variant interpretations issued to patients has not been visible. However, very recent studies are shining a light on the magnitude of the problem. Legal suits focusing on variant interpretation are just beginning to be reported by the media. Please visit our News page.

Why isn’t the government trying to fix the problem of inaccuracies in clinical genetics? 2017-09-07T16:40:42+00:00

The USA and other governments are funding research consortia efforts towards improving the accuracy of genetic variant interpretation. Please visit the Our Approach page for a diagram of some of these government-funded efforts. Thanks to these efforts, we can finally begin estimating the false positive rate for variant interpretation across the clinical genetics industry. However, government-funded projects tend to be prolonged, and diffuse efforts are relying heavily on the volunteer efforts of overburdened and underappreciated clinical scientists. While government-funded efforts can accomplish projects that commercial companies cannot, these projects often move slowly and have delayed impact on clinical genetics patients. For many patients, this delay is the difference between life and death. It is the genetic variant interpretations of commercial diagnostic laboratories that impact patients the most. Commercial diagnostic laboratories have high patient volume and issue variant interpretations at an incredibly fast pace. To have the greatest impact on improving care for genetics patients, CGI has developed a non-profit and non-competing business model that serves patients directly but also serves the commercial diagnostic laboratories. CGI does this by providing laboratories with timely and more accurate variant interpretations at decreased expense to the laboratory. CGI achieves an economy of scale that no single laboratory can achieve and thus can improve the quality of variant interpretations while simultaneously driving down the expense to the patient. CGI works with market forces to achieve its goals, rather than sideways to them. CGI is the deep tech humanitarian organization bridging the gap between the commercial industry and government funded academic projects. By bridging this gap, CGI and its commercial and academic partners can best save and improve the lives of the greatest number of genetics patients. CGI’s mission is the very definition of translational medicine.

Are CGI’s research-use-only genetic variant classifications and reclassifications guaranteed accurate? 2017-09-07T16:40:06+00:00

CGI strives to provide the most accurate variant classifications and reclassifications to its partners and customers. However, like all clinical science, CGI cannot be perfect. As stated within the ACMG guidelines, “Variant analysis is at present imperfect and the variant category reported does not imply 100% certainty.”

Why does CGI keep using the term “for research-use-only” for its services? 2017-09-07T16:39:31+00:00

For a variant interpretation, or for any of CGI’s services to be clinically actionable, a qualified and appropriately certified clinician must officially review and approve the data for the clinical application. CGI does not replace the clinical professional. Rather, CGI provides services to patients and their clinicians, and board certified medical directors, for research purposes. These professionals may or may not choose to use all or part of CGI’s research in their scope of clinical practice. The clinical professional takes on the medical liability for any application of CGI’s research services.

What is a genetic variant, and is it the same as a mutation? 2017-09-07T16:38:38+00:00

A genetic variant is an alteration or deviation in a person’s DNA from a reference DNA sequence. Everybody has many genetic variants. Most variants are benign, meaning they do not cause disease or early death, but some do. The variants that do cause or increase the risk of disease or early death are considered “pathogenic.” The term “mutation” is sometimes used synonymously with “variant,” though sometimes “mutation” is used to mean only those variants which are considered pathogenic. The term “variant” is sometimes incorrectly used to refer only a “Variant of Uncertain Significance (VUS).”

Is “variant interpretation” the same as “variant classification”? 2017-09-07T16:38:09+00:00

For the purposes of CGI’s website, the terms “variant classification” and “variant interpretation” are equivalent. In genetic testing, frequently these terms are interchangeable. However, some clinical contexts these terms have slightly different meanings. For example, a clinician may “interpret” a given variant classification in context of guiding clinical care. In this situation, the two terms have different meanings.

What are the different clinical classifications, or interpretations, of genetic variants? 2017-09-07T16:37:36+00:00

Genetic variants are most frequently labeled with the terms Pathogenic, Likely Pathogenic, Variant of Uncertain Significance (VUS), Likely Benign or Benign. The terms Pathogenic and Likely Pathogenic for certain diseases are generally considered “positives,” while the terms Likely Benign and Benign are generally considered “negatives.” A variant of Uncertain Significance (VUS) is a variant for which there is insufficient data for interpretation or conflicting data. Most VUS is ultimately discovered to be benign, though a very small fraction proves to be positive. Some laboratories use slightly different terms. Also, for recessive (Likely) Pathogenic variants, a person may be described as a “Carrier” if they only have one copy of a positive variant, when a pair of positives in the same patient are needed to express the disease.

What are “false positives” and “false negatives”? 2017-09-07T16:36:57+00:00

Once accurately detected, a genetic variant in a person’s DNA must be clinically interpreted. A “false positive” interpretation means that the variant is reported as increasing risk for disease or early death, when in fact the variant does not increase risk. A “false negative” occurs when a variant is reported as not increasing risk for disease or early death, when in fact it does increase risk. A “Variant of Uncertain Significance (VUS)” is a classification indicating that a clinical meaning of either positive or negative is not yet possible to make due to insufficient evidence.

What is a Variant of Uncertain Significance (VUS)? 2017-09-07T16:36:33+00:00

A variant of Uncertain Significance (VUS) is a variant for which there is insufficient data for interpretation or conflicting data. Most VUS is ultimately discovered to be benign, though a very small fraction proves to be positive. For some VUS, through CGI’s VUSolve®, CGI may be able to assist the patient in driving research towards the discovery of a clinical classification as either Likely Benign or Likely Pathogenic.

What can be done about a Variant of Uncertain Significance (VUS)? 2017-09-07T16:35:48+00:00

While CGI’s Variant FactChecker™  second opinion service is of the highest value for variants described by laboratories as positive, some patients and their clinicians also wish to receive a second opinion on VUS through CGI’s Variant FactChecker service. This service is research-use-only. CGI’s big data approach to variant reclassification is designed to solve the clinical meaning of many VUS over time. Additionally, for some VUS, through CGI’s VUSolve®, or CGI Concierge Service, CGI may be able to assist the patient in driving more rapid research towards the discovery of the true clinical meaning of a VUS.

Does CGI share findings in ClinVar and publications? 2018-04-19T15:27:11+00:00

Yes, CGI will submit variant classifications to ClinVar. CGI is also dedicated to publishing key findings in peer-reviewed literature to promote advancements across the variant interpretation industry.

If CGI is a non-profit humanitarian organization, how can it charge for services? 2017-09-11T15:42:47+00:00

A 501(c)(3) tax-exempt company is not able to provide services in exchange for a donation. However, a 501(c)(3) tax-exempt company can charge for services provided those services are in line with its non-profit mission. While CGI actively seeks donor funds, its service charges allow CGI to provide high impact services, while driving towards eventual self-sustainability to save more lives.

How can a patient in the USA find a certified genetic counselor? 2017-09-07T16:34:10+00:00

Please visit the website of the National Society of Genetic Counselors or your insurance provider list.

Is Variant FactChecker™ HIPAA compliant? 2017-09-13T15:10:52+00:00

HIPAA (Health Insurance Portability and Accountability Act of 1996) is a United States legislation that provides data privacy and security provisions for safeguarding medical information. CGI does maintain personal information privacy and security measures as per CGI’s Terms of Service (link). Personal health information freely provided to CGI, either through the website, through data uploads, email communications, or other means, is not subject to HIPAA guidelines. As such, all CGI services, including Variant FactChecker™, are fully compliant with HIPAA data privacy and security provisions. Learn more about your rights under HIPAA.