My favorite thing about my role as a Genomic Science Liaison (GSL) at Ambry is that I get to apply my training in genetic counseling and experience working in an oncology clinic to conversations with healthcare providers about genetic testing and technology, helping them make the most informed decisions for their patients. In this blog, I have the pleasure of discussing Gene-Disease Validity (GDV), an important concept that is not talked about enough when evaluating hereditary cancer multigene panel tests (MGPTs).  

When designing a hereditary cancer MGPT, labs consider several factors. One is the spectrum of hereditary cancer risks. For example, targeted MGPTs focus on specific types of cancer, such as breast and gynecologic cancers (e.g., Ambry's BRCANext^® panel). Broader MGPTs, also known as pan-cancer MGPTs, include genes linked with risks for various cancers (e.g., Ambry's CancerNext^® and CancerNext-Expanded^® panels). Another is the available evidence supporting a gene’s association with hereditary cancer. For instance, “definitive genes” are genes with a well-established association with hereditary cancer whereas “limited genes” are genes that may have been linked to hereditary cancer based on early studies but lack sufficient evidence to have a clear association. This is where GDV comes into play. 

What is Gene-Disease Validity?  

Gene-disease validity (GDV) refers to the strength of the relationship between a gene and a  disease (e.g. specific cancers). For example, the BRCA1 gene has “definitive GDV” as mutations in this gene are well-known to increase the risk for breast and ovarian cancer. Conversely, genes with less well-understood associations have “limited GDV.” A prime example is the NBN gene, which was previously thought to be associated with an increased risk for breast cancer based on limited evidence. However, as more data from case-control studies emerged, it was shown not to be associated and is now considered “disputed." This means a link between a gene and a disease has been disproven.  

When definitive genes are included in a MGPT, it enhances the clinical utility of the genetic test. Clinical utility refers to a genetic test's ability to provide valuable information for cancer surveillance, management, and/or prevention. Understanding GDV when curating a hereditary cancer MGPT leads to more precise and actionable outcomes, reducing the likelihood of inconclusive or uncertain results. 

Ambry's Approach  

Ambry Genetics has a dedicated team of experts focused on GDV, ensuring that our hereditary cancer MGPTs are both informative and up to date. This involves: 

•    Adding genes: Based on the latest scientific evidence and guidelines, new genes may be added to panels when additional studies confirm their association with cancer risk.  
•    Removing genes: Genes may be removed from panels if further studies do not support their link to cancer risk, helping to reduce the rate of variants of uncertain significance (VUS). 
•    Categorizing genes: Some clinicians and patients prefer that tests only include well characterized genes. Others are comfortable with the uncertainty that can come with limited evidence genes.  Ambry offers limited evidence gene “add-ons” to some tests (i.e. BRCANext, ColoNext^®, CancerNext-Expanded) so that clinicians can choose whether to include limited evidence genes.   

Understanding GDV is crucial when choosing a hereditary cancer MGPT. Ambry utilizes GDV to design more informative and clinically useful genetic tests, ultimately aiding healthcare providers in offering better care and guidance to their patients.