Expert second opinion service* for the interpretation of your clinical genetic variants.
*For research use only.
Will Variant FactChecker™ Help Me
Variant FactChecker is most useful to you if you have received a Positive or VUS result from a recent or past genetic test.
For Positive Patients
The Variant FactCheckerTM report can flag potential false positives on your original genetic test report that may have happened because of over-interpretation of sequence variants. CGI will also provide you it’s research-use-only second opinion variant classification. You should share your Variant FactCheckerTM report with your clinician.
For VUS Patients
For your Variants of Uncertain Significance (VUS), Variant FactCheckerTM research may uncover data that has not yet been evaluated by the originating laboratory. This may facilitate the clinical reclassification of your variant within the originating laboratory.
Variant FactChecker™ Features
You can download a sample FactChecker™ result
How It Works
FAQs (Frequently Asked Questions)
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.
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.
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.
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.
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.
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.
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.
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.
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.”
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).”
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.
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.
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.
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.
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Please visit the website of the National Society of Genetic Counselors or your insurance provider list.
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