BCRF-Supported Study Clarifies Risk Potential for 7,000 BRCA2 Variants

Practice-changing findings may improve risk assessment and personalize treatments for patients

A major BCRF-supported study published in Nature is poised to change genetic testing, risk assessment, and personalized treatment for patients with BRCA2 mutations.

Researchers used CRISPR/Cas9 targeting to analyze an astounding 7,000 BRCA2 variants to determine which variants increased cancer risk and which did not. These variants are found in a key functional part of the BRCA2 gene. Of these, about 5,500 were what are called variants of uncertain significance (VUS), those whose impact on cancer risk and health isn’t clearly established. The research team classified 785 variants as pathogenic or likely pathogenic and about 5,600 variants as benign or likely benign leaving only 608 VUS remaining.

“It was then possible to classify many of these variants as cancer causing or as variants with no influence on cancer risk,” said Dr. Fergus Couch, a BCRF researcher since 2007 and lead investigator on this study.

Many breast cancer patients who undergo genetic testing learn that they have a VUS or several of them—causing anxiety and confusion. As research has slowly unraveled the risk profiles of some VUS, patients are notified that their VUS has been “reclassified,” giving them more clarity.

“VUS in the BRCA2 gene are a substantial problem for patients and clinical providers because no one knows what to do with the uncertain information,” Dr. Couch said. “It’s a big source of stress for patients, who often cannot help thinking that maybe the variant does actually increase their risk of cancer even though their clinical providers should essentially ignore the finding.”

This study represents a major leap forward because of the sheer number of VUS that were assessed. Technology like CRISPR has rapidly accelerated the pace at which VUS can be analyzed.

Next, an expert panel from the National Institutes of Health’s ClinVar database will review the team’s data and begin reclassifying VUS. Dr. Couch and his team classified 261 variants that were previously VUS as pathogenic; ClinVar’s Expert Panel Review has established 14 pathogenic BRCA2 variants to date.

For patients, this study will have a direct impact on care. As these variants are validated and added to ClinVar over time, affected patients will be notified about reclassified VUS in their testing reports, empowering them to discuss changes in their cancer risk with their providers—and potentially take action. This study also has implications for breast cancer treatment. By classifying these VUS, clinicians may be able to identify more patients who may benefit from targeted therapies like PARP inhibitors.

BCRF’s Chief Scientific Officer Dr. Dorraya El-Ashry said these findings are important for women of color and especially Black women, who face worse outcomes after a diagnosis. A retrospective study found that Hispanic and Asian patients tended to have the highest number of VUS on their genetic testing reports, but Black patients had the highest number of variants associated, or likely associated, with cancer. Black women are also more likely to have BRCA2 mutations compared to white women.

“Most previous studies on genetic mutations in breast cancer have been conducted in white women, so non-white women tend to have more variants that have not been investigated,” she said. “These findings improve our understanding of VUS in all women but are especially illuminating for Black women and other people of color who have them.”

This collaborative, multi-institution study comes from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium, which has already produced several important findings, including a 2021 paper that represented the first large, multi-center study to improve breast cancer risk assessment for women without a family history.

“BCRF has provided support to my research team for ongoing genetic studies of breast cancer. Using these funds, we have been able to make significant advances in our understanding of inherited breast cancer,” Dr. Couch said. “Over the last three years, BCRF has directly supported this research project aimed at classifying variants in the BRCA2 gene, along with support from the National Institutes of Health and Mayo Clinic. The project, the findings, and the impact for patients with these variants would not have been possible without the generous support of BCRF.”