This article has been updated to add more details on Ambry's reduced penetrance pathogenic variant reporting policy.
NEW YORK – The authors of a paper published this month want to establish reduced penetrance pathogenic variants (RPPVs) as a new category of BRCA1/2 variants associated with a lower risk of hereditary breast cancer than high-penetrance variants and that carriers of RPPVs should be managed differently.
In the paper, published in npj Precision Oncology, researchers sought to provide a framework to standardize the interpretation and reporting of BRCA RPPVs. The researchers worked with Myriad Genetics and Ambry Genetics, which Tempus AI is acquiring from Konica Minolta, to identify 16 BRCA1/2 variants that both labs agreed had reduced penetrance.
Current guidelines from the National Comprehensive Cancer Network recommend surgeries to reduce the risk of breast cancer in carriers of pathogenic variants in genes strongly associated with inherited cancers, such as BRCA1 and BRCA2. At the pathogenic variant level, the NCCN, for the most part, doesn't make specific management recommendations based on whether patients carry high- or low-penetrance variants in BRCA1/2. The guidelines mention only one BRCA1 RPPV at present.
"What we're saying in our paper is that there are some BRCA1 and BRCA2 mutations that really don't warrant the same management recommendations as the typical high-penetrance BRCA1 or BRCA2 mutations," said Tuya Pal, first author of the npj Precision Oncology study and professor of medicine in the division of genetic medicine at Vanderbilt University.
Penetrance is used to describe the likelihood that a clinical condition will occur when a particular genotype is present. Generally, carriers of pathogenic variants in BRCA1/2 are thought to have around a 60 percent lifetime risk of developing breast cancer compared to a 13 percent risk in the general population. The research published in npj Precision Oncology was spurred by findings over the years showing that not all pathogenic variants in BRCA1/2 are associated with the same level of breast cancer risk. Although germline BRCA1/2 pathogenic variants are associated with a heightened risk of breast, ovarian, pancreatic, and prostate cancer, the authors of the paper focused only on breast cancer risk.
Researchers started noticing a lower breast cancer incidence among some carriers of germline BRCA1/2 pathogenic variants, said Alvaro Monteiro, senior author of the study and senior member in the Population Sciences Division at the Moffitt Cancer Center. "As the years went by, people started having doubts about some of the BRCA1/2 pathogenic variants that they found because they were atypical and did not conform to the traditional pathogenic variants," Monteiro said. "What we started seeing as more people started testing is that now you have these variants that when you actually look at the family history and personal history, they really don't conform [to prior cancer risk estimates] and yet it looks like they are pathogenic."
BRCA1/2 RPPVs are associated with a more moderate risk for breast cancer compared to the traditional high-penetrance BRCA1/2 variants, meaning that fewer carriers of these reduced penetrance variants will go on to develop the disease. Yet the BRCA1/2 RPPVs still confer a higher risk of developing breast cancer compared to non-carriers in the general population.
In the npj Precision Oncology analysis, the researchers explored the concordance of BRCA1/2 RPPVs reported by Myriad and Ambry, which have different approaches to classifying these variants. To determine reduced penetrance, each lab applied its cancer history weighting algorithms, which compare the cancer histories of individuals with a variant of interest to carriers of known pathogenic variants in the same gene and to individuals with no known pathogenic variants.
After the labs each provided sets of BRCA1/2 RPPV candidates based on their own datasets, the researchers compared them for concordant interpretations and identified 16 that both labs agreed were RPPVs. These RPPVs included missense, splice site, and frameshift variants in BRCA1 and BRCA2, while traditional high-penetrance BRCA1/2 pathogenic variants tend to be protein truncating variants.
The researchers then independently evaluated the 16 RPPVs for pathogenicity and evidence of reduced penetrance. "One of the labs we worked with used Fanconi anemia [a genetic blood disorder] as one of the criteria to determine pathogenicity, while the other lab did not, but they have a really robust family history tool. One of labs uses RNA data more than the other one does," Pal said. "There are some subtle differences, but they ultimately came to the same conclusion [that these 16] variants had reduced penetrance."
Some of the RPPVs identified in the study have been explored separately in previous studies. In a 2018 paper, for example, researchers evaluated the breast and ovarian cancer risk associated with the BRCA1*R1699Q variant, which the two labs and the researchers also identified as an RPPV in the npj Precision Oncology analysis. The 2018 paper estimated that around 20 percent of women carrying this variant would develop breast cancer by age 70, conferring an intermediate risk.
A patient with an RPPV in BRCA1 or BRCA2 is at risk of overtreatment if their physician follows current NCCN guidelines for managing breast cancer risk, since the guidelines are written for carriers of traditional BRCA1/2 pathogenic variants, said Pal. "That finding of 20 percent lifetime risk [for an intermediate risk variant] is very different from typical BRCA1 and BRCA2 variant's lifetime cancer risk," Pal said. "That level of risk [from the BRCA1*R1699Q variant] is not high enough to warrant a risk-reducing mastectomy, for example."
Similarly, in a 2022 paper, researchers reported that patients with missense pathogenic variants in BRCA1/2, like those identified in the npj Precision Oncology paper, had lower cancer risk compared to those with protein truncating variants in BRCA1/2.
Based on increasing data in the literature and that two large genetic testing labs in the US can already identify these variants, Monteiro, Pal, and colleagues believe that RPPVs are ready to be considered a unique risk category with clinical management recommendations that differ from those for high-penetrance BRCA1/2 variants. Moreover, they want the field to start thinking of the risk associated with BRCA1/2 variants as a continuum.
"For the purposes of clinical management, you have to have specific cut offs, and right now we just have pathogenic or not pathogenic," Monteiro said. "So, we thought that one way to move towards the idea that BRCA1/2 variant risk is a continuum is to create this third category [of reduced penetrance variants], which has intermediate risk but also triggers some clinical management."
Currently, labs typically classify BRCA1/2 variants as pathogenic, likely pathogenic, uncertain, likely benign, or benign based on available evidence, but labs have different policies regarding which of these categories of variants they include in patient reports. Some labs for example, only report pathogenic or likely pathogenic variants, while others report variants of uncertain significance as well. Similarly, how labs report more nuanced risk estimates within the pathogenic category and indicate if a variant has high or low penetrance is also not standardized in the industry.
Myriad, for example, currently reports BRCA1/2 RPPVs as variants with "special interpretation," the company said in a comment. The goal of this designation is to alert providers that these variants are different than other pathogenic variants [in BRCA1/2], the company said.
"Reports for these variants also include specific language indicating the cancer risks associated with the variant are expected to be lower than with typical pathogenic variants," Myriad said in a statement.
Ambry also includes information about the varied risk of cancer from RPPVs in its reports, Marcy Richardson, associate director of clinical research at Ambry and an author on the npj Precision Oncology paper, said in an emailed statement.
"We include clear, bolded risk statements in our reports, such as: 'Risk estimate: Current risk estimates associated with this variant are not well defined and may be variable, ranging from negligible to high-risk HBOC [hereditary breast and ovarian cancer]. Clinical correlation is advised.' This ensures clinicians have the most nuanced and actionable information possible," Richardson explained.
She added that the company is engaged in discussions to unify terminology around RPPVs. "As the field evolves, achieving consensus on how to classify and communicate these variants will be critical for patient care," Richardson said.
Monteiro and Pal's team is working closely with Myriad, Ambry, and other genetic testing labs to find ways to harmonize how RPPVs in BRCA1/2 are reported in genetic testing results. They hope to create a framework of concordant methods for classifying and reporting these RPPVs across labs.
They hope further research into the RPPVs identified in their study will also lead to updates in variant databases, such as ClinVar, to reflect their lower risk of cancer and the different clinical management needs of BRCA1/2 RPPV carriers.
The ClinVar database currently describes some of the BRCA1/2 RPPVs in the paper only as a pathogenic variant, Pal said. For clinicians to get a full picture of what these variants mean, they would need to read each of the studies referenced in the ClinVar entry, which can be a challenge for a busy oncologist, Pal added.
Monteiro and Pal acknowledged that there needs to be further research on BRCA1/2 RPPVs to spur changes in guidelines, at labs, and in variant databases. It will be important to determine penetrance estimates for each of the RPPVs from large cohorts, they said, though they noted that the rarity of these variants in the population may make such studies difficult.
They also hope to explore RPPVs in other hereditary cancers, such as ovarian cancer, and in other cancer susceptibility genes, such as CHEK2 and ATM. Finally, research is also needed to assess if breast cancer patients with BRCA1/2 RPPVs respond differently to PARP inhibitors than those with high-penetrance variants.
For now, Pal urges clinicians to look out for these 16 RPPVs in their patients and consider the lower breast cancer risk associated with them in their clinical management decisions. NCCN guidelines currently only mention one BRCA1 variant, R1699Q, that confers a reduced risk for breast cancer compared to high-penetrance variants. For the BRCA1 R1699Q variant, the NCCN notes that the risk of developing cancer is about 24 percent and recommends individualizing risk management based on the patient's personal and family history.
The study authors also suggest that carriers of BRCA RPPVs may benefit from more complex risk assessment models that incorporate risk-associated single-nucleotide variants aggregated into polygenic risk scores, which may provide a more complete picture of their lifetime cancer risk.
"Clinicians don't have an easy way of identifying these variants right now," Pal said. "It’s something we need to figure out structurally, how do we get this information into the databases, so people don't have to look at our paper. What I would say, for now, is that all BRCA variants are not equal."