️ Episode 145: A Validated Highly Sensitive Microsatellite Instability Assay Identifies PMS2 Variants in CMMRD

In this episode of PaperCast Base by Base, we explore a study that validates a next-generation sequencing-based highly sensitive microsatellite instability (hs-MSI) assay for the diagnosis of constitutional mismatch repair deficiency (CMMRD), a rare childhood-onset cancer predisposition syndrome. The work focuses on improving detection of PMS2 pathogenic variants, the most frequent but technically challenging cause of CMMRD.

Study Highlights:
The researchers applied the hs-MSI assay to a blinded cohort of 66 blood and 24 tumor samples from individuals with CMMRD and controls, demonstrating a sensitivity of 98.5% and specificity of 100% in detecting the syndrome. The hs-MSI results showed strong correlation with whole-genome low-pass instability scores (LOGIC/MMRDness) and identified distinct microsatellite indel patterns that differentiated PMS2 variant carriers with an accuracy of 0.997. Higher hs-MSI scores were also associated with earlier age of tumor onset, highlighting its potential role as a biomarker for cancer risk stratification.

Conclusion:
This validated hs-MSI assay provides a robust and clinically feasible tool to support CMMRD diagnosis, distinguish PMS2 involvement, and personalize surveillance strategies.

Reference:
Marín F, Canet-Hermida J, Bianchi V, Chung J, Wimmer K, Foulkes W, et al. A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency. *Clinical Chemistry*. 2024;70(5):737–746. https://doi.org/10.1093/clinchem/hvae027

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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