Genetic testing plays a critical role in the delivery of personalized medicine. Take, for instance, hereditary cancer, where genetic testing can help inform treatment and other management decisions for both individuals with an active cancer diagnosis and those at an increased risk for cancer. For the latter, genetic testing helps minimize their risk by allowing them to engage in early detection and preventive options. 

For genetic testing to be effective, laboratories must distinguish disease-causing changes (pathogenic variants) in our DNA from the benign variations that make us all unique. In some cases, it’s relatively straightforward to characterize variants as pathogenic (e.g., if a large part of a gene is missing). However, in most cases, an in-depth review of available evidence is needed to make this determination. Sometimes, evidence may be either insufficient or conflicting–in these cases, variants are classified as having unknown significance (VUS), which equates to an inconclusive result.

Inconclusive results are challenging for patients and providers as they generate uncertainty surrounding the explanation for cancer in a family, cancer risk counseling, and recommendations for risk management or treatment. In an effort to reduce inconclusive results, we founded Ambry’s Translational Genomics (ATG) lab to actively generate evidence that may help reclassify VUS as pathogenic or benign, providing more clarity for patients and healthcare providers. The ATG lab focuses on a specific type of evidence called functional evidence, which provides an idea of whether a variant impacts a gene’s function.

In a recently published study in JAMA Network Open, we present findings from the ATG lab’s experience offering RNA genetic testing for individuals with certain types of inconclusive results from DNA hereditary cancer testing. Of 56 different VUS studied, RNA genetic testing results helped resolve 88% as either disease-causing (47%) or benign (41%). Upon surveying the ordering clinicians, we found that clinical management recommendations changed for 44% of patients and 78% of families as a result of these variant reclassifications.

In one of these cases, a patient received an inconclusive DNA testing result for MSH6, a gene associated with the hereditary cancer condition Lynch syndrome, which is associated with an increased risk for uterine and colorectal cancer. RNA genetic testing results revealed the presence of abnormal RNA, which provided additional evidence needed to reclassify the variant as likely pathogenic and confirm a diagnosis of Lynch syndrome. The patient and her sister, who also tested positive for the variant, decided to undergo surgery to prevent subsequent gynecologic cancers from developing, and both will also receive frequent colonoscopies to screen and reduce their risk for colorectal cancer. Other family members who test positive for this variant will also benefit from early detection & cancer prevention options.

In this study, we also reviewed results from over 300,000 patients who had previously received DNA testing for hereditary cancer at our lab to estimate how often we encounter variants that could be clarified with RNA genetic testing. It turns out that 1 in 43 patients (2.4%) could benefit from RNA genetic testing.

Key Takeaways from the study:

• RNA genetic testing provided additional evidence needed to reclassify variants, which ultimately impacted clinical care by increasing the diagnostic yield and decreasing the inconclusive rate.
• Variants that can be clarified by RNA genetic testing are frequent among patients who receive DNA testing for hereditary cancer, so this additional testing has the potential to impact 1 in 43 patients tested.
• Currently, a major limitation to the effectiveness of RNA genetic testing is its overall availability —in the study, samples were only submitted for 10% of patients who were offered RNA genetic testing as a follow-up to DNA testing. This is most likely due to the logistical challenges of coordinating additional testing after a patient has already received DNA testing results. 

To increase patient access to the benefits of RNA genetic testing, Ambry Genetics has launched +RNAinsight – in which DNA and RNA testing are performed at the same time. Learn more about +RNAinsight here. 

Read the complete study from JAMA Network Open .

Contact us if you are interested in learning more about genetic testing.