A validation of models for prediction of pathogenic variants in mismatch repair genes

Genet Med. 2022 Oct;24(10):2155-2166. doi: 10.1016/j.gim.2022.07.004. Epub 2022 Aug 23.


Purpose: Models used to predict the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, are widely used. Recently, MMRpro was updated with new colorectal cancer penetrance estimates. The purpose of this study was to evaluate the predictive performance of MMRpro and other models for individuals with a family history of colorectal cancer.

Methods: We performed a validation study of 4 models, Leiden, MMRpredict, PREMM5, and MMRpro, using 784 members of clinic-based families from the United States. Predicted probabilities were compared with germline testing results and evaluated for discrimination, calibration, and predictive accuracy. We analyzed several strategies to combine models and improve predictive performance.

Results: MMRpro with additional tumor information (MMRpro+) and PREMM5 outperformed the other models in discrimination and predictive accuracy. MMRpro+ was the best calibrated with an observed to expected ratio of 0.98 (95% CI = 0.89-1.08). The combination models showed improvement over PREMM5 and performed similar to MMRpro+.

Conclusion: MMRpro+ and PREMM5 performed well in predicting the probability of having a pathogenic homozygous or heterozygous variant in a mismatch repair gene. They serve as useful clinical decision tools for identifying individuals who would benefit greatly from screening and prevention strategies.

Keywords: Colorectal cancer; Lynch syndrome; Mismatch repair; Model combination; Model validation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Colorectal Neoplasms, Hereditary Nonpolyposis* / diagnosis
  • Colorectal Neoplasms, Hereditary Nonpolyposis* / genetics
  • DNA Mismatch Repair* / genetics
  • Germ-Line Mutation / genetics
  • Heterozygote
  • Humans
  • Mismatch Repair Endonuclease PMS2 / genetics
  • MutL Protein Homolog 1 / genetics


  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1