MAVEs to the rescue in the fight against breast cancer

In honor of breast cancer awareness month, we’d like to dedicate this post to exploring how MAVEs can ensure that breast cancer is detected as early as possible. A study estimated the national cost-savings in the United States from early cancer diagnosis at $26 billion per year1. If you are not yet familiar with MAVEs (Multiplexed Assays of Variant Effect), you can check out our previous two blog posts (Introduction to MAVEs and Opportunities and Challenges to Using MAVEs for Clinical Variant Interpretation) that give an overview of the topic. In short, MAVEs are experiments that enable large-scale collection of information on the clinical impact of thousands of genetic variants found in the human population. How can such information help to ensure early detection?

You may be aware of BRCA1 and BRCA2, the two most notorious breast cancer risk genes. In the almost 30 years since their discovery2,3, variants of BRCA1 and BRCA2 have been established as strong risk factors for breast cancer. What you may not know is that thousands of unique BRCA1 and BRCA2 variants have been observed in humans (see the ClinVar database entry for BRCA1). While some variants are highly pathogenic, conferring a 70% chance of the disease by age 804, other variants are completely benign. To complicate the matter, the majority of observed variants have unknown clinical impact. In other words, it is unclear if they are pathogenic or benign when it comes to conferring breast cancer risk. These variants are termed Variants of Uncertain Significance (VUS).

Receiving a BRCA1 or BRCA2 VUS result from a genetic test can be confusing and anxiety-provoking for patients and their doctors because recommendations for screening and preventive treatment depend on pathogenic or benign variant classifications. For example, some healthy patients with pathogenic variants will choose to have prophylactic surgery, or to undergo more frequent mammograms. In contrast, a benign variant is reassuring because it indicates that an individual is not at increased risk due to this specific variant. A VUS is generally inactionable and can result in a lack of critical screening and preventive care on the one hand (in the case that the VUS is actually pathogenic) or unnecessary anxiety and overreaction on the other hand (if the VUS is actually benign).

Enter MAVEs to the rescue5. Through large scale experiments on thousands of variants, MAVEs provide crucial information about how each variant affects gene function and, thus, how it might impact cancer risk. This information can be applied as evidence towards pathogenic or benign classifications according to the guidelines established by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP)6. High-quality MAVEs have been performed for BRCA1 and BRCA2, and one study demonstrated that this information could be used to reclassify 69% of BRCA1 VUS observed by a clinical laboratory7. By classifying VUS as pathogenic or benign, patients and their physicians can confidently make screening and treatment decisions to ensure early detection and potentially reduce risk of serious disease.

Although MAVEs have been demonstrated to be highly impactful, they are widely underleveraged in variant classification workstreams at diagnostic laboratories due to challenges of finding the data, evaluating assay quality, and transforming raw data into evidence. Constantiam’s MAVEvidence platform enables efficient and confident application of MAVE data by curating all data within a searchable platform, performing an independent evaluation and analysis of each assay, and calibrating evidence strength for use within the ACMG/AMP variant classification framework. MAVEvidence generates a report for each variant, outlining evidence from all of the available MAVE studies, with a concise analysis and explanation of the data. Thus, MAVEvidence overcomes the major hurdles to leveraging MAVE data in the clinic, reducing the number of VUS results and increasing productivity of variant scientists (by 90%), in turn enabling precision screening and preventive treatment for more patients.

How can I get started using MAVE-derived evidence in my variant classification workflows?

If you’re interested in integrating MAVE-derived evidence into your variant classification workflows, head over to the MAVEvidence page to learn more and sign up for a free trial today. For more personalized guidance or if you have specific questions, feel free to reach out to us at [email protected]. Our team is always available to assist you with integrating MAVE-derived evidence into your variant classification workflows.

1. Kakushadze, Z., Raghubanshi, R. & Yu, W. Estimating Cost Savings from Early Cancer Diagnosis. Brown Univ. Dig. Addict. Theory Appl. 2, 30 (2017).
2. Wooster, R. et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265, 2088–2090 (1994).
3. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).
4. Breast cancer risk factors you can’t change. https://www.cancer.org/cancer/types/breast-cancer/risk-and-prevention/breast-cancer-risk-factors-you-cannot-change.html.
5. Starita, L. M. et al. Variant Interpretation: Functional Assays to the Rescue. Am. J. Hum. Genet. 101, 315–325 (2017).
6. 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. 17, 405–424 (2015).
7. Fayer, S. et al. Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN. Am. J. Hum. Genet. 108, 2248–2258 (2021)