145: hs-MSI Validation: Detecting CMMRD and Pinpointing PMS2

Marín F et al., Clinical Chemistry - This episode examines a validation study of a highly sensitive NGS-based microsatellite instability (hs-MSI) assay for diagnosing constitutional mismatch repair deficiency (CMMRD). The assay was tested on blinded blood cohorts and CMMRD-associated tumors, compared with a low-pass whole-genome LOGIC/MMRDness score, and evaluated for gene-specific MSI indel patterns that identify PMS2 biallelic carriers. Key terms: microsatellite instability, CMMRD, PMS2, hs-MSI assay, genetic diagnostics. Study Highlights:The hs-MSI assay was validated in blinded blood and tumor cohorts with very high accuracy for CMMRD detection (sensitivity ~98.5% and specificity 100%). Hs-MSI scores correlated strongly with LOGIC/MMRDness scores (r = 0.89 in blood, r = 0.82 in tumors). Analysis of indel allele distributions distinguished biallelic PMS2 pathogenic variant carriers with an accuracy of 0.997 and higher hs-MSI scores associated with younger age at first tumor diagnosis (r = −0.43). Conclusion:The hs-MSI assay is an accurate ancillary diagnostic tool for CMMRD that can detect MSI in blood and tumors and help pinpoint PMS2 as the affected germline gene. Music:Enjoy the music based on this article at the end of the episode. Article title:A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency First author:Marín F Journal:Clinical Chemistry DOI:10.1093/clinchem/hvae027 Reference:Marín F, Canet-Hermida J, Bianchi V, 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. doi: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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/a-validated-highly-sensitive-microsatellite-instability-assay-identifies-pms2-variants-in-cmmrd QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-09-22. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited sections cover the hs-MSI assay development, 192-marker MSI panel, comparison with LOGIC/MMRDness, indel signatures distinguishing PMS2 carriers, performance metrics (sensitivity/specificity), cross-tissue detection (blood and tumor), and clinical implications for therapy and surveillance.- transcript topics: Constitutional mismatch repair deficiency (CMMRD) overview; PMS2 gene, pseudogenes, and diagnostic challenges; highly sensitive MSI (hs-MSI) assay development; 192-microsatellite panel versus LOGIC/MMRDness; indel (insertion/deletion) signatures by affected gene; PMS2 signature as diagnostic marker (0.997 accuracy) QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- hs-MSI uses a panel of 192 microsatellites; threshold 4.57% used to call posi... Chapters (00:00:00) - A revolutionary cancer diagnostic tool for CMMRD(00:03:39) - The genetic test for CMMRD(00:07:27) - HS MSI assay: 100% specificity and 99% sensitivity(00:10:24) - Immunity of CMMRD: a genotype specific fingerprint(00:13:51) - HS MSI score for CMMRD