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/

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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 positive MSI status
- blood-based hs-MSI detected CMMRD with ~98.5% sensitivity and 100% specificity
- hs-MSI scores correlated with LOGIC/MMRDness scores (r = 0.89 in blood; r = 0.82 in tumors)
- PMS2 carriers show a distinctive indel signature with higher insertions; overall PMS2-indel accuracy 0.997
- hs-MSI detected MSI in all 24 tumor samples analyzed (across multiple organ origins)
- higher hs-MSI scores in blood correlated with younger age at first tumor (r = -0.43)

QC result: Pass.