+RNAinsight: A Year in Review

Since October 2019, +RNAinsight has revolutionized germline genetic testing for hereditary cancer and has provided clinically actionable results to many patients and families who may have otherwise received a negative or inconclusive result from DNA-only testing. Here are some highlights from the first year.

+RNAinsight: Paired DNA and RNA Genetic Testing

+RNAinsight improves the sensitivity and clarity of genetic testing. It works in tandem with Ambry Genetics’ DNA testing to identify patients with or at-risk for hereditary cancer who might otherwise be missed, decrease variants of unknown significance in real-time, and provide more accurate results to inform patient care.1,2

DNA-Only Testing May Miss Patients At-Risk For or With Hereditary Cancer

Many patients suspected to have hereditary cancer receive negative or inconclusive results due to limitations of DNA-only genetic testing. While there have been several advancements in genetic testing since the days of Sanger sequencing, there is still a need to enhance variant detection and interpretation. Adding simultaneous RNA genetic testing to DNA-only tests with +RNAinsight is the next step to providing more accurate, actionable results to patients and their families.

Genetic Testing Technology Timeline – DNA and RNA:

Genetic testing timeline

Paired DNA and RNA Testing Improves Variant Detection and Classification

Add RNA genetic testing to a hereditary cancer panel for every patient undergoing DNA testing to deliver more clinically actionable results.

+RNAinsight Provides an Additional Line of Evidence To:

Identify More Patients with Hereditary Cancer1
Decrease Variants of Unknown Significance1,2
Provide More Accurate Results to Inform Patient Care1,2

Identify More Patients with Hereditary Cancer

Find Patients That May be Missed by DNA-Only Testing

Clinical diagnostic labs typically apply a reporting range limit to their DNA genetic testing panels. Variants outside these ranges have a much lower probability of being pathogenic (disease-causing) and would most often be classified as a variant of unknown significance (VUS). Looking beyond these ranges would only increase the VUS rate without increasing the diagnostic yield. However, using +RNAinsight expands the reporting range of DNA-based testing, which in turn enables Ambry to provide a clear diagnosis to more patients who may otherwise be missed.1

Decrease Variants of Unknown Significance in Real-Time

Patients undergoing hereditary cancer testing may receive a VUS result, which can cause uncertainty and confusion for both the ordering healthcare providers and patients. A VUS result does not provide actionable information to inform medical management since it doesn’t clarify if the patient is at an increased risk for cancer. +RNAinsight provides an additional line of functional evidence that can tip the scale towards pathogenic or benign.1-3 In some cases, this additional evidence can turn a VUS into an actionable positive or clear, negative result.

Provide More Accurate Results to Inform Patient Care

A negative report or a VUS can be unsettling, especially in the background of a strong cancer history. Patients may worry that a mutation was missed by current technology, or that there may be a mutation in another gene. A VUS could be benign or it could be pathogenic. Ambry’s experience since 2016 with retrospective RNA genetic testing in Ambry’s Translational Genomics (ATG) Lab demonstrates that this additional evidence can give families and healthcare providers greater confidence that their report is truly negative or that the variant classification is the most up-to-date and accurate.

RNA Genetic Testing Decreases Variants of Unknown Significance

3 Years of Experience in The ATG Lab2


+RNAinsight Product Overview

Available to order with hereditary cancer panels*

Genes eligible for RNA:


14-21 day turnaround time (No increase due to +RNAinsight)**

Sample Requirements:

One kit that includes 1 EDTA tube (DNA) and 1 PAXgene® tube (RNA)

*+RNAinsight is not available with BRCAplus® or TumorNext tests. CustomNext-Cancer® can be used for single syndrome/single gene testing orders.
**Orders including +RNAinsight are not eligible for STAT testing.

Technical Details

Ribonucleic acid (RNA) is isolated from the patient’s specimen using standardized methodology and quantified. RNA is converted to complementary DNA (cDNA) by reverse transcriptase polymerase chain reaction (RT-PCR). Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and Next-Generation sequencing. RNA transcripts are screened for 18 genes (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2 exons 1-10, PTEN, RAD51C, RAD51D, and TP53) and compared to a human reference pool. The absence or presence of RNA transcripts meeting quality thresholds is incorporated as evidence towards assessment and classification of DNA variants. Any regions not meeting RNA quality thresholds are excluded from analysis.

+RNAinsight: Learn More about the Benefits of DNA and RNA Genetic Testing


1. Ambry Genetics, internal data on file
2. Karam R. et al. RNA Genetic Testing in Hereditary Cancer Improves Variant Classification and Patient Management. ACMG 2019.
3. Richards S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24

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