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BRCA2 Variants of Unknown Significance Reclassified Through Functional Data Additions

NEW YORK – The addition of functional data can help reclassify germline variants of unknown significance within the DNA binding domain of BRCA2, a new study has found.

Pathogenic germline variants in BRCA2 increase a person's risk of developing a number of cancers, particularly breast and ovarian cancer. Knowledge of such a pathogenic or likely pathogenic germline variant can influence how the person is screened for cancer as well as inform any later treatment, such as PARP inhibitor therapy, should the person develop cancer. 

But according to the Mayo Clinic's Fergus Couch, there are more than 4,500 VUS in BRCA2 listed in the NIH ClinVar database, representing about half of the BRCA2 variants listed there. "This means that many thousands of tested individuals around the world have these variants but do not know their clinical significance and cannot use them to select clinical management approaches," he wrote in an email.

Couch and his colleagues used a homology-directed DNA repair assay to gauge whether some 250 VUS affecting the BRCA2 DNA binding domain were functional. By combining these findings with variant classifications made by their collaborators at Ambry Genetics, they could reclassify most VUS as either likely pathogenic or pathogenic or as likely benign or benign, as they reported on Friday in the American Journal of Human Genetics.

From ClinVar, the researchers selected 252 VUS that affect the DNA-binding domain of BRCA2 for functional analysis. That domain, Couch noted, is where most pathogenic missense BRCA2 mutations are located. Through an HDR assay, they found 90 of the VUS to be non-functional and 162 to be functional.

The HDR assay is considered a gold-standard assay, according to the researchers, who also noted it is weighted as a strong line of evidence in the American College of Medical Genetics and Genomics/Association for Molecular Pathology-based variant classification scheme. Of 49 variants analyzed by both HDR assays and previously by quantitative classification models, the researchers reported 48 had concordant results.

At the same time, 186 of these 252 variants had been observed by Ambry Genetics, which classified 154 of them as VUS. By folding in HDR assay protein functional data, the researchers reclassified 86 percent of the variants initially determined to be VUS. In particular, 132 were reclassified to be either likely pathogenic or pathogenic and 93 to be likely benign or benign. Only 22 variants remained classified as VUS, and those had either limited or conflicting data.

The reclassification of these VUS affected results for 1,900 individuals who were tested at Ambry, the researchers added. This shift in classification, Couch said, could change how individuals are monitored or treated for cancer. He added that if someone now has a variant considered to be likely pathogenic or pathogenic, that person could pursue avenues such as more frequent mammograms or even prophylactic mastectomy or oophorectomy. For individuals with cancer, he noted that those with ovarian cancer or metastatic breast cancer would now qualify for targeted therapy with PARP inhibitors.

The findings further suggest, Couch said, that other VUS could similarly be re-evaluated with HDR and other assays. He and his colleagues are working toward that end to gather information about all the possible variants in this region and are further investigating whether the variants affect response to therapies like PARP inhibitors.

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