From Uncertainty… 

Cassidy: When I met with my patient in late 2021, she had already faced bilateral breast cancer. First at age 52, and again in the other breast at age 55. In terms of family history, she only had a brother who was diagnosed with brain cancer and testicular cancer, so her family history didn’t indicate there was a strong suspicion for hereditary cancer. However, since she herself had two primary cancers, she met guidelines for genetic testing; so, I ordered Ambry’s BRCANext^® test.  

When her results arrived, we learned that my patient had a Variant of Uncertain Significance (VUS) in the BRCA2 gene, which means there were no specific clinical actions recommended based on the test results at that time. 

…To Clarity… 

Cassidy: In early 2025, my Ambry Genomic Science Liaison (GSL), Amanda Jacquart, CGC, proactively reached out to let me know that Ambry had additional data and scientific evidence that led to the reclassification of my patient’s BRCA2 VUS; it had been upgraded to “Likely Pathogenic Variant.”  

This significantly altered my patient’s risk profile. It means she now has: 

• an explanation for her history of bilateral breast cancer 
• an increased risk for ovarian cancer (including fallopian tube cancer): lifetime risk 13%-29%¹
• an increased risk for pancreatic cancer: lifetime risk 5%-10%² 

Without this BRCA2 reclassification, and the proactive outreach by my Ambry GSL, we wouldn’t have known there was a genetic mutation that increased my patient’s risk for cancer. We especially wouldn’t have known that she was at increased risk for ovarian and pancreatic cancers as well. As a two-time breast cancer survivor with no known family history of ovarian or pancreatic cancer, this result transforms her approach to cancer screening, prevention, and surveillance moving forward. 

…To Action. 

Cassidy: This BRCA2 variant reclassification unlocked preventive screening and risk-reducing options for my patient’s consideration, including: 

• Annual Breast MRIs 
• Risk-reducing bilateral mastectomy (surgical removal of breasts + breast tissue) 
• Risk-reducing bilateral salpingo-oophorectomy (surgical removal of fallopian tubes and ovaries) 
• Pancreatic cancer screening 
• Participation in a hereditary cancer program  

Additionally, sharing this information with her nieces and nephews was critical for her, ensuring they’re informed of their potential cancer predisposition and the recommendation to get genetic testing. 

What Roles Did MAVEs Data and Classifi Play in Upgrading this BRCA2 Variant? 

Amanda: When I reached out to Cassidy, I explained that her patient’s VUS was recently upgraded to likely pathogenic, thanks to new functional evidence from a recent study published in Nature. This study used high-throughput saturation genome editing to characterize thousands of BRCA2 variants, providing the critical data needed to demonstrate this specific variant's loss of function and support its reclassification.  

Ambry has been supporting MAVE studies with our extensive clinical data since 2019, with more on the horizon. MAVEs (Multiplex Assays of Variant Effect) are high-throughput, functional studies which are often designed to include up to all potential single nucleotide variants in a clinically significant gene or protein domain—in this case, BRCA2. They allow scientists to analyze thousands of variants in a single experiment. They generate functional scores which can then be translated into evidence for variant classification or reclassification. And that’s where the Ambry Classifi program comes in. Ambry has released a new white paper on the topic, which delves deeper into how the MAVEs data and Classifi can lead to impacting thousands of patients through initial classifications and reclassifications. 

References:  

1. Kuchenbaecker K et al. JAMA. 2017 Jun 20;317(23):2402-2416 

2. Chaffee K et al. Genet Med. 2018 Jan;20(1):119-127