Abstract
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
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Article info
Publication history
Published online: August 23, 2022
Accepted:
July 1,
2022
Received in revised form:
June 30,
2022
Received:
April 7,
2022
Footnotes
Danielle Braun and Giovanni Parmigiani are co–last authors and contributed equally.
Identification
Copyright
© 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
