Researchers utilize funtional test to quantify the impact of inhertited varient in BRCA2 acancer gene

Researchers utilize funtional test to quantify the impact of inhertited varient in BRCA2 acancer gene


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  • Source: Mayo Clinic

  • Date: 21 Feb,2021

Researchers at Mayo Clinic have combined results from a functional test measuring the effect of inherited variations in the BRCA2 breast and ovarian cancer gene with clinical information from women who received genetic testing to determine the clinical importance of many BRCA2 variants of uncertain significance (VUS). The findings were published today in a study in the American Journal of Human Genetics.

“There are 4,565 distinct VUS in the BRCA2 gene listed in the National Institutes for Health (NIH) Clinical Variant Database,” says Fergus Couch, Ph.D., a breast cancer researcher at Mayo Clinic. The database lists versions submitted by genetic testing labs and research groups.

Dr. Couch says the 4,565 variants represent about 50% of all reported BRCA2 variants in the NIH database. He says many thousands of people examined around the world have these variations, but they don’t have any way to understand the clinical significance of their specific variants. And their doctors have no way to use this information to pick methods for preventing breast or ovarian cancer, or to choose targeted treatment approaches for tumors with BRCA2 alterations.

The current method for attempting to determine the clinical relevance of BRCA2 variants of uncertain significance relies on a series of rules from the American College of Medical Genetics and Genomics ACMG/AMP that use genetic information about the variants and information from patients and patients’ families.”

Dr. Fergus Couch, Researcher, Mayo Clinic

Dr. Couch and his team employed a functional test to ascertain the effect of several VUS on BRCA2 DNA damage repair activity. They first showed that the functional test was able to discriminate between known pathogenic cancer-causing variations and known benign BRCA2 variants which do not increase risk of cancer.

“We found that 86% of the VUS we surveyed were reclassified as benign or sterile, which is an important step forward from the 10 percent or so missense variations in the DNA binding domain which have previously been classified,” says Dr. Couch. “This is the first time that a practical test was combined with ACMG/AMP data this manner, and the results demonstrate it is highly effective.”

Dr. Couch says the results will have a positive effect on patient care because patients will understand whether breast cancer VUS are benign or pathogenic.

“Patients whose VUS are benign will now be assessed based on their personal and family history of ovarian and breast cancer, rather than on the basis of the genetic testing outcome,” states Dr. Couch. “And patients that are classified as having pathogenic variants will have the ability to benefit from more frequent cancer screening or prophylactic mastectomy to decrease risk of developing breast cancer.”

The findings also mean that women with ovarian cancer today may know whether they would qualify for targeted therapy with PARP inhibitors.

Journal reference:

Richardson, M.E., et al. (2021) Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-binding-domain variants of uncertain significance. American Journal of Human Genetics.

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