In the field of genetic counseling and testing, the stories of patients and the healthcare professionals who guide them through their journeys are as compelling as they are educational. Recently, I had the privilege of working with Alyssa Valentine, MS, CGC, a senior genetic counselor at Cook County Health in Chicago, Illinois. In her role in a safety net hospital, she serves a diverse and often underserved patient population, which offers unique challenges and rewards.  

One case in particular highlights the importance of clinicians providing and Ambry leveraging tumor characteristic information for accurate mismatch repair (MMR) gene variant classification.  In blog 1 of this series, “TCLR: Revisiting an Innovative Method for Mismatch Repair Variant Classification,” Jessica Grzybowski, MS, CGC explains how a tumor characteristic likelihood ratio (TCLR) is incorporated into Ambry’s variant assessment framework. Here, I will share insights into a patient case where the incorporation of TCLR resulted in a major impact on MMR gene variant classification. 

A Textbook Case with Uncertain Results 

Alyssa shared the story of a man who was diagnosed with right-sided colon cancer in his thirties, which immediately raised suspicions for Lynch syndrome, a hereditary condition that increases the risk of several types of cancer including colon cancer.  

Immunohistochemistry (IHC) testing on the tumor indicated a loss of MLH1 and PMS2 protein expression, classic hallmarks of this syndrome. However, germline testing in 2021 revealed an MLH1 variant of uncertain significance (VUS), leaving the patient and his medical team in a diagnostic limbo. 

The initial discovery of a VUS, rather than providing clarity, often leads to frustration for both providers and patients. "You want an answer for your patient," Alyssa explained, underscoring the desire to offer specific management recommendations and next steps for the patient as well as their family. Alyssa recounts, “Especially in the cancer space, I found that the first question for most of my patients is, ‘What about my family members?’” The uncertainty of how to proceed when facing a VUS is a significant challenge in genetic counseling where the implications extend beyond the patient to their relatives.  

Collaborative Efforts Lead to Clarification 

The turning point in this case came a few years later when the patient's oncologist, suspecting something more, sought out Alyssa to investigate further. They opted for MLH1 hypermethylation testing on the tumor block, which returned no evidence of hypermethylation, ruling out one of the likely somatic (or sporadic) explanations for the IHC deficiency.  

After a consultation with a genetic counselor at Ambry, microsatellite instability (MSI) testing was then performed. This is an additional screening test that can help clarify whether a tumor is more likely to be caused by Lynch syndrome. It revealed the tumor was MSI-high, aligning with the suspicion of this condition. 

Armed with this new information, Alyssa reached out to her contacts at Ambry, sharing the updated tumor characteristic findings. Ambry was then able to leverage TCLR in the variant assessment, which led to the reclassification of the MLH1 VUS to a variant likely pathogenic (VLP), which is considered a positive result for Lynch syndrome. This collaborative effort between the clinic and the lab provided the patient and his family with much-needed answers. 

Continuing to Strive for Clear and Actionable Results 

This case underscores several key aspects for seeking accurate MMR gene variant classification. First, it spotlights the importance of tumor characteristic information in variant assessment for patients with histories suspicious for Lynch syndrome. Additionally, it shows the value in persistence and pursuing further tumor testing if the initial germline results are inconclusive. It also illustrates the profound impact of collaboration among healthcare professionals, including genetic counselors, oncologists, and laboratory scientists, in achieving accurate diagnoses. Alyssa shares, “Never feel like you can't call the people at the lab. They're there to help you [...] the insight that the lab GC was able to provide was really essential.” 

Through this patient’s story, we're reminded of the collaborative efforts by healthcare professionals to guide patients through uncertainty toward clarity and actionable information. Watch Alyssa’s interview and hear more about this unique patient case.