Powerful new analyzes could improve breast cancer risk assessment on a large scale

Imagine you have a history of breast cancer in your family and want to get a better idea of ​​your personal risk. You see your doctor and he recommends that you get tested to see if you have a genetic variant that would increase your risk of developing breast cancer. After weeks of nervous waiting, the results come in and you learn that your BRCA 1 and 2 variants, the genes associated with breast cancer risk, are… of “unknown clinical significance.”

Melissa Cline, a researcher at the UC Santa Cruz Genomics Institute and program manager for the BRCA Exchange platform that consolidates data on BRCA 1 and 2 genetic variants, hears this kind of story all the time. There are approximately 34,000 known BRCA gene variants that have been reported in clinical trials according to the NIH ClinVar repository, and more than a third of these variants are of uncertain clinical significance, meaning we do not know their impact on a person’s risk. of breast cancer could be.

“I get emails from women who have discovered they have a variant of unknown significance and they are concerned and want to know what I can tell them about their variant,” Cline said.

Previously, Cline wasn’t able to tell them much, but she and her team are now rolling out a powerful new feature to BRCA Exchange that will make risk assessment much easier. In agreement with the ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium, they provide “provisional evidence code assignments,” computer-generated analyzes that will help scientists determine whether a given variant is pathogenic or no for thousands of people previously. unclassified variants.

While these analyzes are “interim” until they can be reviewed by ENIGMA ClinGen’s Variant Curation Expert Panels (VCEPs), the official expert body for BRCA variant curation, the evidence code assignments they provide have been carefully reviewed by both VCEP coordinators. and BRCA Exchange developers and are unlikely to change after review by biocurators. This means that clinicians will already be able to use many of these designations as guidelines when helping their patients make decisions about preventative care.

Cline herself is a “presurvivor,” the term for someone who is at increased genetic risk for breast cancer but has not yet developed symptoms of the disease. Knowing her risk has allowed her to take precautions, like increasing the frequency with which she gets mammograms, and has given her a greater sense of control over her health. She is very pleased that BRCA Exchange is now able to share interim data which will allow more people with previously unknown levels of risk to have more clarity about the risk they are at.

New evidence codes follow strict guidelines

BRCA Exchange is able to deploy the interim data because the ENIGMA consortium’s ClinGen Variant Curation Expert Group (VCEP) just released its variant curation standards in August. The work is published in The American Journal of Human Genetics.

These objective standards are based on more general guidelines from the American College of Medical Genetics (ACMG) and the Association for Molecular Pathology (AMP) that have been used to describe how variants in various genes can be classified as benign , probably benign, pathogenic, or probably pathogenic.

Cline is a member of the ENIGMA VCEP and says part of the challenge in analyzing BRCA variants of unknown significance is that the guidelines are very complex to account for a lot of in-depth knowledge of the nuances of genes BRCA, and therefore difficult to apply.

“We were initially prompted to take on this project because the rules for evaluating variants are not easy to apply manually,” Cline said. “Even biopreservatives had problems with them.”

The detailed nature of the standards made variant evaluation an ideal candidate for computational analysis to systematically apply them for each of the variants in their database. Cline and his team are revealing the proof codes they calculated under the new rules. Evidence codes are broken down into those that support a benign (labeled B) or pathogenic (labeled P) classification, as well as a ranking of the strength of that evidence, from “very strong” to “favorable.”

The codes fall into several categories, each providing a different piece of evidence indicating the likelihood that a variant is pathogenic. Recently, the team published the evidence codes for the “population frequency” evidence category. The more frequently a variant appears in the human population, the more likely it is to be benign, and Cline estimates that demographic evidence alone will be strong enough to rule out the possibility of increased breast cancer risk for nearly 3,000 BRCA variants.

Later this calendar year, the BRCA team plans to combine population frequency evidence codes with interim evidence codes for zero variation and computational prediction. These codes analyze genomic evidence to see if a variant causes a loss of function, which would make the variant likely pathogenic; or conversely, if the variant belongs to a class of variants that do not disrupt function and are rarely pathogenic, which would suggest that the variant is benign. The combination of population proof, null, and computer prediction codes is expected to provide insight into tens of thousands of variants.

Although people from all backgrounds will benefit from the clarity provided by these assessments, statistically the impact of reducing the number of variants of unknown meaning will be felt most strongly among populations of non-European origin.

Indeed, historical inequalities in research participation and access to testing and treatment have made variants more common in non-white populations less likely to be studied, leading to higher percentages of “variants of unknown significance” among non-white populations. European ancestry. This disparity in turn means that many people of non-European ancestry have fewer options for understanding and managing their hereditary cancer risk.

“An interesting possibility is that this work catalyzes the curation of variants by laboratories in places around the world that do not have a majority white population,” Cline said. “To date, people of African, Asian, and Hispanic descent have a high rate of variants of uncertain significance due to historical disparities in research, and I am hopeful that our work here could help reduce these disparities .”

To further expand the scope of variant assessments, BRCA data will also now be available on a new BRCA Exchange track hub hosted by the UCSC Genome Browser. This hub provides all variants and provisional code assignments in a genomic context, but with a user interface that many scientists are already accustomed to using. Cline hopes this center will help accelerate both continued research into BRCA variants and the use of evidence codes by clinicians and genetic counselors.

“We anticipate that BRCA Exchange data will be used by clinical reference laboratories to help them screen for new BRCA variants they see in their patients,” Cline said. “It’s going to have a huge impact and bring peace of mind to a lot of people.”