While other initiatives have successfully established databases of mutations for many different genes, “the major hurdles to the quality of most open gene databases are curation, data sharing from private laboratory companies performing real-world patient testing (versus academic research), and the long term financial sustainability,” Dr Beroud wrote.
“BRCA Share provides a new model that solved all those issues. It provides free access to data for research purposes and is open to new partners to share data, with commercial members funding administrative, curation, and other costs based on a sliding fee. This will eventually result, in the next few years, in great amounts of information that will allow for the classification of variants, facilitating data interpretation, genetic counseling, and patient information.”
In his presentation at the 6th Biennial Meeting, Dr Beroud told attendees that the BRCA Share database now contains variant data for more than 35,000 BRCA1/2 gene sequence tests from the largest clinical labs in the United States and France. During the past year, 505 new BRCA1 mutations, an increase of 25%, and 865 new BRCA2 mutations, a 30.7% increase, have been added. Of these, 21.6% of BRCA1 mutations and 16.7% of BRCA2 mutations were identified as pathogenic.
The mutation profiles for all phenotypes are classified as having large or small rearrangements (including missense) or mid-intronic variations, with the biological significance of each classified as “neutral,” “likely neutral,” “VUS” [variant of unknown significance], “likely causal,” or “causal.”
“A VUS is a mutation for which evidences for classification are not strong enough,” Dr Beroud wrote. “The data sharing from multiple partners improves our knowledge and thus the chances to collect additional evidence (new families with segregation information, new data about co-occurrence) for this specific mutation, which together may end up with sufficient data for classification.
“The thousands of mutations collected in BRCA Share allow for potentially improved genetic counseling and identification of risk by reducing the number of VUS. As such, it facilitates mutation interpretation and therefore the identification of at-risk women, thus allowing them to be counseled about guidelines for prevention and early diagnosis, including management of screening and options for risk reduction.”
Of the 342 BRCA1 VUS submitted to date, 37.8% could be reclassified based on evidence provided by the partners, with the majority becoming “neutral” (23.3%), or “likely neutral” (69%). Similarly, 32.7% of BRCA2 VUS could be reclassified. The initiative is “currently developing a prioritization system for VUS selection for reclassification,” particularly for those that “are close to the edge,” Dr Beroud noted.
Wendy H. Bost, director of corporate communications for BRCA Share co-founder Quest Diagnostics in Madison, New Jersey, told Cancer Therapy Advisor in an email that “by clarifying the cancer risk of BRCA variants, BRCA Share is helping to enhance the quality of patient testing.”