Name:
McCarthy- Making Sense of Genetic Testing Results
Description:
McCarthy- Making Sense of Genetic Testing Results
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Upload Date:
2022-02-27T00:00:00.0000000
Transcript:
Language: EN.
Segment:0 .
Hi everyone, I'm Jeanette McCarthy from Precision Medicine Advisors and in this brief video we'll learn about making sense of results from genetic testing.
Segment:1 Diagnostic/Predisposition Testing.
Dozens of academic and commercial labs currently offer sequencing of gene panels for diagnosing and predicting hereditary conditions like breast cancer. These tests involve sequencing anywhere from a few to dozens of genes where mutations in the gene are known cause of disease; genes like BRCA1 and BRCA2. The sequencing method used for these tests allows one to identify not only well established disease causing mutations or variants, but previously unknown disease-causing variants as well.
Segment:2 Not All Variants are Pathogenic.
Gene panel testing is likely to uncover sequence variants in just about everybody who's tested, but it's important to know that not all genetic variation in our genomes is disease causing or pathogenic. In fact, most of the approximate 4 million sequence variants found in the average person are harmless. Even variants located in disease genes are not all pathogenic. So what are some of the clues that a variant in a disease gene is pathogenic?
Well, most variants in our genome are common, shared with many healthy individuals in the population. Pathogenic variants are more likely to be rare and found only in people with the disease. Pathogenic variants are also more likely to alter the structure of the protein, ranging from something as simple as a single amino-acid change to more drastic alterations in protein length. Pathogenic variants are more likely to alter the function of the protein causing it to lose its ability to bind a ligand, dimerize, or fold, for example.
We can use computer programs to predict whether a variant is likely to alter the protein function but direct evidence from in vivo or in vitro laboratory experiments are required for definitive proof.
Segment:3 Clinical Evidence.
Perhaps the most compelling evidence that a variant is pathogenic is having observed it previously in patients with the same disease and not in healthy individuals. While not sufficient in and of itself to declare pathogenicity, this evidence is typically weighted very heavily.
But knowing this vital piece of information, whether a specific variant has been seen before in a patient or not, is only possible if that information is shared. The most common source of shared genetic information from testing laboratories is the public database ClinVar but not all laboratories submit their results to this resource.
Segment:4 Multiple Lines of Evidence.
Determining whether a variant found in a disease gene in a patient is pathogenic or benign is one of the most challenging aspects of genetic testing.
Classification of variants is never based on one piece of evidence, but instead relies on careful weighting of multiple lines of evidence to make a determination of pathogenicity.
Segment:5 Variant Classification Schemes.
Different laboratories may use different criteria and different weights to assess pathogenicity, but many are based, in principle, on guidelines proposed by the Association of Molecular Pathologists and the American College of Medical Genetics and Genomics. Most variant classification schemes attempt to classify variance as clearly pathogenic or benign, but more often than not the evidence is not sufficient to classify the variant with certainty.
In these cases, that uncertainty is reflected in classifications of "likely pathogenic," "likely benign" or the dreaded "variant of uncertain significance."
Segment:6 How to Interpret a Test Result.
Laboratory reports from genetic testing typically present findings of a pathogenic or likely pathogenic variant as a positive test result. These are relatively easy to interpret. If the test finds no variants in the gene, or only likely benign or benign variants, the test result is considered negative.
Finally, if a variant of uncertain significance is found, it's typically reported as such or sometimes, not reported at all. These last two categories are often misinterpreted by patients and physicians alike.
Segment:7 Interpreting ‘Negative’ Results.
First, let's consider the negative genetic test result. It's important to keep in mind that unless a test is focused on a specific pathogenic variant known to be carried by the patient's family members, a negative test result simply means that the test did not detect a pathogenic variant in the genes present in the testing panel.
The patient has a residual risk of disease that may be similar to the risk before they got tested, and the reason is twofold. First of all, hereditary forms of common diseases like breast cancer typically account for only a small percent of disease five to ten percent, unordered, for breast cancer. Most breast cancer is not hereditary, despite a family history. Second, even among hereditary forms, our knowledge about which genes are involved is limited.
We know the genes involved in only about half of hereditary cancer. Our understanding of the genetic basis of cancer and other common diseases will improve over time as more people are tested, but for now, a negative test result is based on our limited understanding of the disease.
Segment:8 VUS are Often Misunderstood.
Variants of uncertain significance are also prone to misinterpretation and are often found in the course of sequence-based testing. For example, about five to ten percent of patients undergoing testing for BRCA1 and BRCA2 receive a VUS result.
In some cases, there's a tendency to overinterpret a VUS as being likely pathogenic. In one study, for example, 21% of patients with a VUS in BRCA1 or BRCA2 went on to have a prophylactic oophorectomy to prevent ovarian cancer. A VUS can be under-interpreted as well which may be the case in a high-profile lawsuit where a patient was tested for mutations in a known epilepsy gene, given a VUS result, and consequently treated as if they had a different disorder.
VUS's are, in fact, equally likely to be pathogenic as they are to be benign.
Segment:9 Classifications Can Change Over Time with More Evidence.
Because variant interpretation considers evidence available at a given point in time, it's possible that the classification could change over time. Variants that were previously of uncertain significance could be reclassified as pathogenic or benign. When selecting a laboratory to conduct genetic testing, make sure you're clear about their reclassification policies how often the variants are reclassified, and how that information is communicated to the ordering physician.
For more information about diagnostic and predisposition testing including a guide on variant interpretation, check out our new book from McGraw-Hill Education called "Precision Medicine A Guide to Genomics in Clinical Practice"
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