Table 4 Ancillary tests for assessing constitutional MMR deficiency.

From: ERN GENTURIS guidelines on constitutional mismatch repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management

Validated test#

CMMRD confirmed

CMMRD refuted

Germline Microsatellite instability (gMSI) testing acc. to Ingham et al. [28].a

gMSI ratios of at least two (usually all three) microsatellite markers are above the validated laboratory’s internal thresholds

Not possible by the test

Constitutional MSI (cMSI) testing acc. to Gallon et al. [25, 26].b

cMSI score above the validated laboratory’s internal thresholds

cMSI score within the score range of negative controls

High-sensitivity MSI (hsMSI) testing acc. to González-Acosta et al. [27].c

hsMSI score above the validated laboratory’s internal thresholds

hsMSI score within the score range of negative controls

Ex vivo MSI (evMSI) + methylation tolerance acc.to Bodo et al. [22].d

evMSI and methylation tolerance above the validated laboratory’s internal thresholds

evMSI and methylation tolerance within the range of negative controls

MMRDness testing by low-pass whole-genome sequencing/ LOGIC assay in blood leukocytes acc. to Chung et al. [24].e

MMRDness score above the validated laboratory’s internal thresholds

MMRDness score within the score range of negative controls

  1. MMR Mismatch repair, CMMRD Constitutional mismatch repair deficiency, MSI microsatellite instability, acc. according, PV pathogenic variant, (L)PV (likely) pathogenic variant.
  2. #Validation cohort should include (i) at least eight CMMRD patients with different genotypes with respect to PVs and affected gene (for each of the four MMR genes at least one patient should be included), (ii) a large number of negative controls consisting of at least twenty adult individuals aged > 40 years without cancer history and without a MMR gene (L)PV, (iii) at least ten confirmed MMR gene PV heterozygotes and, if available, (iv) POLE and POLD1 PV heterozygotes.
  3. aIngham et al. Simple detection of germline microsatellite instability for diagnosis of constitutional mismatch repair cancer syndrome. Hum Mutat 2013; 34:847–52.
  4. bGallon et al. A sensitive and scalable microsatellite instability assay to diagnose constitutional mismatch repair deficiency by sequencing of peripheral blood leukocytes. Hum Mutat 2019; 40(5):649–655.
  5. bGallon et al. Constitutional microsatellite instability, genotype, and phenotype correlations in Constitutional Mismatch Repair Deficiency. Gastroenterology 2023; 164(4):579–592.
  6. cGonzález-Acosta et al. High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers. J Med Genet 2020; 57(4):269–273.
  7. cMarín et al. A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency. Clin Chem 2024; 70(5):737–746.
  8. dBodo et al. Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite instability and Lymphocyte Tolerance to Methylating Agents. Gastroenterology 2015; 149:1017–29.
  9. eChung et al. Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset. J Clin Oncol 2023; 41(4):766–777.
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