Uncovering Breast Cancer Risk Beyond a Standard BRCA Genetic Test
A Triple-Negative Breast Cancer Diagnosis That Raised Questions
In 2021, a woman in her early 50s was diagnosed with triple-negative breast cancer (TNBC) in her right breast. She underwent surgery followed by chemotherapy and is now in remission. While her recovery brought relief, it also raised important concerns about her family’s future. With two daughters aged 27 and 20, she began to question whether her diagnosis had a hereditary component. Although her mother had breast cancer at age 82 and there was no significant cancer history on her husband’s side, TNBC itself is strongly associated with inherited genetic mutations, particularly in the BRCA1 gene.
The First Step: BRCA Genetic Test
Step one was completing the BRCA genetic test to determine her risk for having an inherited predisposition to breast and/or ovarian cancer. An evaluation by BRCA Genetic Testing includes sequencing both the BRCA1 and BRCA2 genes. BRCA genetic testing is considered the gold standard for investigating a person's risk for developing hereditary breast and/or ovarian cancer.
Both BRCA1 and BRC-2 genes help repair damaged DNA, and if either the BRCA1 or BRC-2 gene is mutated, the person's lifetime risk of getting cancer rises substantially. Her BRCA genetic test results were negative (i.e., there were no clinically significant variants identified). For someone with negative BRCA genetic test results, this news is typically met with relief; however, because of the considerable concern associated with triple-negative breast cancer (TNBC) when diagnosed at a young age (under 60 years), there remains clinical concern despite having received negative BRCA genetic test results.
The reason some people continue to express concern despite previously receiving negative BRCA genetic test results relates to the limitations of standard DNA sequencing. Standard sequencing uses DNA sequencing technology to detect small genetic deformities. Examples of these small alterations would be a single nucleotide change, or the small insertion or deletion of a number of nucleotides. Large rearrangements (e.g., large deletions or duplications) of genomic DNA, or structural variations, may also cause significant disruptions to the function of genes in the same manner as smaller mutations. However, large genomic rearrangements require specialized testing techniques to detect them.
Given her diagnosis of TNBC and the level of continued concern expressed by her clinicians, they ordered additional testing (i.e., testing with the Multiplex Ligation-dependent Probe Amplification (MLPA) technology). The Role of MLPA in Detecting Hidden Mutations MLPA is specifically designed to identify large deletions or duplications that may be missed by a routine BRCA genetic test based solely on sequencing. In her case, MLPA analysis revealed a known pathogenic deletion in the BRCA1 gene.
This finding confirmed that she carries a mutation associated with a significantly increased lifetime risk of breast and ovarian cancers. The initial negative BRCA genetic test had not provided the complete picture, but comprehensive testing uncovered the underlying genetic cause.
What This Means for Her Daughters
The identification of a pathogenic BRCA1 mutation has important implications for her family. Her daughters now have the option to undergo predictive BRCA genetic testing to determine whether they have inherited the mutation.
If they test positive, they can begin enhanced screening at an earlier age, consider breast MRI surveillance, and discuss preventive strategies with healthcare professionals. Instead of uncertainty, they now have access to clear, actionable information that supports proactive healthcare decisions.
Genetic testing encompasses many more tests than just BRCA testing. Although BRCA testing is an essential first step for assessing hereditary breast cancer risk, other gene mutations put individuals at risk for developing breast cancer. Specifically, individuals with negative BRCA testing who have significant clinical suspicion for hereditary breast cancer should undergo multigene panel testing which can elucidate a comprehensive assessment.
A model for comprehensive genetic testing is critical to ensure that lesser-known but clinically significant mutations are not missed. Comprehensive testing assists with personalized surveillance strategies and provides guidance regarding treatment (i.e., targeted therapy eligibility) along with the ability to perform cascade testing for family members.
Moving Beyond Hope and into Knowledge
The case of the patient discussed here demonstrates the importance of evaluating hereditary cancer beyond the result of a BRCA genetic test. More advanced testing methodologies provide an opportunity to identify hidden mutations that may be present on the chromosomes. For this patient, her thorough genetic evaluate provided additional clarity for both herself and her daughters.
Through the thorough evaluation of hereditary cancer risk, families are empowered to make decisions based on knowledge, rather than hope, for their decisions and the decisions of future generations.