Summary
- Genetic testing is accurate in accredited labs
- False positive and false negative results can still occur
- Predictability of a genetic mutation or variant varies significantly depending on the disease and other factors
- The same genetic mutation can lead to varying degrees of severity of disease
- Genes are not fate
Introduction
You got your genetics tested through your employee benefits program with the hope that this will lead to improved health, and your genetics report shows a mutation or variant. Now what? The first question that should come to mind is how accurate is this testing? This is what we will discuss in this month's article.
Accuracy of Genetic Testing
There are two forms of validity to consider when discussing the accuracy of genetic tests:
- "Analytical Validity" is the accuracy of the testing in the laboratory. This helps answer: If the test is abnormal, are you really carrying an abnormal gene? And if the test is negative, are you truly not carrying the abnormal gene?
- "Clinical Validity" means how accurate is the genetic test to predict that a disease or drug side effect will indeed occur or not occur.
Analytical Validity: Lab Error?
In the U.S., the Clinical Laboratory Improvement Amendments (CLIA), or even stricter state requirements regulate laboratory standards. These standards ensure appropriate lab quality control to ensure the tests that your doctor is relying on to treat you are indeed accurate. Genetic testing done in CLIA certified laboratories is very accurate but not perfect; false positives and false negatives can still occur.
There are many possible reasons for errors that relate to the lab - for example reagents used or clerical error. Also, not all genetic tests evaluate the entire gene and some types of genetic mutations might not be accurately detected with the testing methodology used. Another problem that can occur is that the specimen that was sent in for analysis might have been inadequate or too small.
Genetic Testing providers also can vary on their interpretation of the genetic findings. This impacts what is reported back to the doctor. The American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) terminology classifies genetic variants as pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, or benign.
It is up to each individual lab to assign each mutation to the various category of results. Fortunately, the concordance rate between reputable certified labs is very good. For example, with the BRCA Breast/Ovarian cancer gene test, a recent study showed that various testing labs agree on their interpretations in 98.5 percent of variant calls.
They say that this agreement in genetic testing interpretation between labs is better than agreement between doctors interpreting mammograms or breast biopsy pathologies.1Another concern is that the results are not always clear-cut 'normal' or 'abnormal'. It is common in genetic testing to find 'variants of uncertain or unknown significance' (VUS) which can be anxiety provoking and perplexing for both the patient and the doctor.
These VUS variants are found in 5 to 10 percent of women who get BRCA genetic testing performed.2 Patients with VUS results are suggested to follow up with their physician or geneticist every year or so, to see if new research has changed the classification of a specific genetic variant as this could result in a change in the way the patient should be managed.
Clinical Validity: Will you get the Disease?
The other area relating to the accuracy of these genetic tests is their clinical validity or predictability. This varies quite a bit depending on the gene and the disease. If you carry a genetic mutation, what is the risk that you will develop that specific disease? We call this 'gene penetrance'. There are some rare single-gene diseases where having the mutation is 100 predictive that you will get the disease such as Huntington's disease.
For the much more common, multi-gene diseases like cardiovascular disease, the risks associated with any specific genetic variant or mutation are relatively low.3 Combining multiple genetic variants together into a 'Genetic Risk Score' is also being studied for many different diseases such as heart disease and diabetes. A 2016 study shows that people with a high genetic risk score for heart disease have about double the rate of heart disease compared to those with a low genetic risk score.4
This level of risk is similar to what we see in most of the other clinically accepted and widely used cardiovascular risk factors.In employee age groups, Genetic Risk Scores add significant risk predictability power along with conventional risk factors.
Genetic testing younger employees might find a subset of the staff who might appear low risk by conventionally lab testing, but actually might be at an increased risk and therefore might benefit from more aggressive preventative screening and/or therapeutics.(5,6) The predictability of a genetic test to determine future risk of developing a disease is also impacted by many other factors:
- Age
- Gender
- Ethnicity
- Family history
- Other genetic factors
- Smoking status
- Lifestyle
- Preventive medicine measures
It is also important to remember that even though your genetics' report states you don't carry a specific genetic mutation or you have a low genetic risk score, you can still develop the disease or drug side effect.
Equally, even though your genetics/DNA stays fairly constant over your lifespan, the report of your genetics can change over time as researchers find new gene-disease risk associations.
Additionally, there are still un-defined genetic factors that contribute to predictability, and new discoveries/revelations of these genetic factors will improve risk scoring and predictability. Therefore, periodic re-analysis should be undertaken.
Expressivity: How Severe is the Disease?
The same genetic mutation can lead to different disease severities in different people. You might be carrying a gene that puts you at an increased risk for baldness, but how bald you will become depends on many other factors.We also see this in some genetic medical diseases like a connective tissue disease called Marfan syndrome.
The features of Marfan syndrome vary widely despite carrying the same genetic mutation. Some people have only mild physical deformities such as being tall with long fingers, but some people with this syndrome develop life-threatening complications affecting the heart and blood vessels.
Conclusion
It is always best to talk to your doctor and/or genetics counselor to fully understand the meaning of your test results for you as an individual. False positives and false negatives can occur. Most importantly, your genes are not fate. There are many preventative measures through increased screening, medications and/or surgeries that can dramatically decrease your risk of developing a disease even if you are carrying a genetic mutation.
Knowing your genetics might also help incentivize you to adopt a healthier lifestyle.In next month's December article, we will discuss the clinical utility (usefulness) of specific types of genetic tests and show how these tests can be incorporated into corporate wellness or voluntary benefits to help improve your employee's health.
I invite you to answer an anonymous one-question survey at the top of the article and see what others think about genetic testing. Also, post your comments and opinions in the comments section below as we start this open discussion.
About Wamberg Genomic Advisors
Wamberg Genomic Advisors is your partner in the Genomic Revolution. Our mission to make genomic testing readily available at prices everyone can afford. Our focus is on delivering genomic products and services to employers and their employees via their trusted benefit brokers and policyholders of life insurance companies.
To discover more about WGA and the future of genomics, visit wamberggenomic.com.
Medical Disclaimer
All content in this article was created for informational purposes only. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician, genetic counselor or other qualified health provider with any questions you may have regarding a medical condition or testing.
Never disregard professional medical advice or delay in seeking it because of something you have read in this article. Reliance on any information provided in this article is solely at your own risk.
Citations
- Lincoln SE et al, Consistency of BRCA1 and BRCA2 Variant Classifications Among Clinical Diagnostic Laboratories. JCO Precis Oncol. 2017 Jul;1
- Murray ML et al, Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: variant reclassification and surgical decisions. Genet Med. 2011 Dec;13(12):998-1005
- Lindor NM et al, Whole-Genome Sequencing in Healthy People. Mayo Clin Proc. 2017 Jan;92(1):159-172
- Khera AV et al, Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. N Engl J Med. 2016 Dec 15;375(24):2349-2358
- Tada H et al, Risk prediction by genetic risk scores for coronary heart disease is independent of self-reported family history. Eur Heart J. 2016 Feb 7;37(6):561-7
- Abraham G et al, Genomic prediction of coronary heart disease. Eur Heart J. 2016 Nov 14;37(43):3267-3278
