Jeanette McCarthy, MPH, PhD
Patients with breast cancer as well as healthy at-risk individuals can benefit from genetic testing to determine whether their cancer is due to an inherited pathogenic variant in a cancer-causing gene. But the results of those tests are not always clear cut.
A 60-year-old woman with a personal and family history of breast cancer underwent genetic testing with a pan-cancer gene panel. This test queried 47 genes associated with a diverse array of cancer syndromes, some but not all of which are known to present as breast cancer in some patients.
The results came back: a variant of uncertain significance (VUS) in DICER1, a gene associated with pleuropulmonary blastoma familial tumor predisposition syndrome.
Uncertain results like these are not uncommon, especially with large gene panels, and might leave patients scratching their heads. Uncertainty in genetic testing stems from several sources: inclusion of limited evidence genes, pleiotropy/variable expression, reduced penetrance and uncertain pathogenicity.
Not all panel genes are definitively associated with breast cancer
The major genes associated with hereditary cancers were discovered around two decades ago, but widespread testing has been available for only about five years. Our knowledge about the relationship between genes and hereditary cancer risk grows with each person tested.
There is a core set of well-established genes where pathogenic variants confer a moderate to high risk of breast cancer. There are also genes that have less evidence supporting their role in breast cancer. Both types of genes appear on large, commercially available gene panel tests.
A recent paper by Lee et. al. graded the top 30 genes found on hereditary breast cancer panels. They found that a third of the genes had insufficient evidence of association with breast cancer.
Moreover, the genes with the strongest evidence tend to have management guidelines (The National Comprehensive Cancer Network has guidelines for 11 breast cancer genes). Less definitive genes have no management guidelines.
Cancer genes exhibit pleiotropy/variable expression
Pleiotropy (the association of a single gene with multiple seemingly unrelated traits) and variable expression (the disease can manifest in different ways) are hallmark features of hereditary cancer genes. For example, the MLH1 gene, most strongly associated with colorectal cancer, is also associated with ovarian, endometrial, bladder, pancreatic and gastric cancers. The evidence of MLH1 association with breast cancer is not as strong.
The DICER1 gene which was present on the pan-cancer panel test used on our patient is known to increase the risk of a variety of cancerous and noncancerous (benign) tumors, most commonly certain types of tumors that occur in the lungs, kidneys, ovaries and thyroid, but not breast cancer. Even if the DICER1 variant were pathogenic, we have no management guidelines or breast cancer risk estimates to give our patient.
Not all hereditary cancer genes are fully penetrant
Penetrance refers to the risk of disease in people with a pathogenic variant. Very few cancer genes are fully penetrant. Instead, most of them increase a person’s risk of disease several-fold above the background risk of cancer in the general population. For any given gene, the penetrance estimates will vary for each associated cancer. For the established breast cancer genes, the penetrance by age 85 ranges from ~22% to ~90%.
Not all variants in cancer genes are pathogenic, or disease-causing
Each variant found in a cancer gene needs to be evaluated to determine whether it is pathogenic or not. The process of variant interpretation takes information about the variant frequency, effect on the protein structure and function and observation in other cases of disease to classify a variant as pathogenic, likely pathogenic, a variant of uncertain significance, likely benign or benign.
In one lab’s experience running cancer panels on >300K patients, about 20% of large cancer panel tests reported a VUS. Most VUS are eventually downgraded to benign/likely benign, but until then, VUS should not be used to make medical decisions.
Given this uncertainty, what is the value of a large panel test?
Large gene panel tests are used most often because of the higher diagnostic yield. One study documented a 50% higher diagnostic yield going from a 2-gene panel to a multi-gene panel, but this increase in diagnostic yield was accompanied by a 1000% increase in VUS results. Insurance companies will generally not cover large gene panels if they contain genes that aren’t supported by guidelines. Yet, testing these genes on large numbers of patients may provide the evidence needed to support or refute their role as cancer risk genes.
In the meantime, health care providers need to deal with the uncertainty that may come with large gene panels.
To learn more about interpreting genetic test reports, enroll in our online Hereditary Cancer Testing course.
 Lee K. et. al. Clinical validity assessment of genes frequently tested on hereditary breast and ovarian cancer susceptibility sequencing panels. Genet Med 2018.
 Richards S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-24.
 Mersch J. et. al. Prevalence of Variant Reclassification Following Hereditary Cancer Genetic Testing. JAMA 2018 Sep 25;320(12):1266-1274.
 Kurian AW. et. al. Uptake, Results, and Outcomes of Germline Multiple-Gene Sequencing After Diagnosis of Breast Cancer. JAMA Oncol 2018 Aug 1;4(8):1066-1072.