TCLR: Revisiting an Innovative Method for Mismatch Repair Variant Classification

In the rapidly evolving landscape of hereditary cancer genetics, precision in classifying genetic variants is crucial. Ambry Genetics recognizes this need and consistently innovates by applying rigorous methods and multidisciplinary expertise to better interpret variants, including for specific gene and variant types that can be more challenging.  

In 2020, Ambry developed a novel method to accurately classify alterations in mismatch repair (MMR) genes​ ​by incorporating a tumor characteristic likelihood ratio (TCLR) into the variant assessment framework (Li et al., 2020). TCLR is a statistical model that quantifies tumor characteristics, including microsatellite instability (MSI) and immunohistochemistry (IHC) results, to assess pathogenicity for germline MMR gene variants. This marked a significant advance in how healthcare providers understand and treat cancers associated with Lynch syndrome. 

Mismatch repair genes are the guardians of genomic integrity, correcting errors that occur during DNA replication. However, pathogenic variants or mutations in these genes can compromise their function, leading to an increased risk of developing cancer. The challenge in testing mismatch repair genes has traditionally been the high rate of variants of uncertain significance (VUS). A genetic variant is classified as a VUS if there is not enough evidence to confirm it is either pathogenic (harmful) or benign (harmless). Medical decisions should not be made based on identification of a VUS, leaving clinicians and patients in a dilemma regarding the best course of action. 

Ambry’s utilization of TCLR in variant assessment provides a solution to clarify the significance of MMR variants by harnessing the power of detailed tumor characteristic analysis (e.g., MSI and IHC results). This approach uses functional evidence to support a more nuanced understanding of each variant's impact, significantly reducing the number of VUSs and leading to more actionable insights for patient care. By integrating comprehensive tumor data and state-of-the-art bioinformatics with TCLR, Ambry created a model that not only improves the accuracy of MMR gene variant classification but also enriches our understanding of their role in cancer development.  

In blog 2 of this series, we will share insights from an interview with genetic counselor Alyssa Valentine. She will detail a specific case in which providing tumor characteristic information enabled Ambry to leverage TCLR, resulting in a major impact on the variant classification for a patient. The patient had a personal history of early-onset colorectal cancer and was “textbook” for Lynch syndrome but did not have a diagnosis until this breakthrough in his case. Reflecting on the consultation from and collaboration with Ambry, Alyssa said, “I think you have this as your model situation where it can significantly impact care and your recommendations for patients and their families. It took a lot of different people and I’m grateful to all the people that I worked with to help me figure out this case.” 

The development and incorporation of TCLR underscores the importance of innovation and rigorous research in genetic testing. It highlights how combining clinical observations with advanced analytical techniques can overcome longstanding challenges in the field. This work moves us closer to a future where genetic testing consistently offers clear, actionable results, empowering clinicians to make informed decisions and offering patients a clearer path to cancer risk reduction, early detection, and personalized treatment. 




Qian, D., Thompson, B. A., Gutierrez, S., Wu, S., Pesaran, T., LaDuca, H., Lu, H.-M., Chao, E. C., & Black, M. H. (2020). Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. Journal of Medical Genetics, 57(1), 62–69. 

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