A comparison of models used to predict MLH1, MSH2 and MSH6 mutation carriers

MMRpro, prediction of mutations in MLH1 and MLH2 (PREMM(1,2)) and MMRpredict are models which were developed to predict the probability that an individual carries a Lynch syndrome-causing mutation. Each model utilizes data from personal and family histories of cancer. To date, no studies have compared these models in a cancer genetics clinic. The purpose of this study was to determine each model's ability to predict the probability of carrying a Lynch syndrome-causing mutation in individuals with a family history of colorectal cancer and to determine their clinical applicability.

We obtained family pedigrees from 81 individuals who presented for Lynch syndrome testing due to a personal and/or family history of cancer. Data from each pedigree were entered into the models and analyzed using SPSS.

We found that MMRpredict, PREMM(1,2) and MMRpro showed similar performances with areas under the receiver-operating characteristic curve of 0.731, 0.765 and 0.732, respectively. MMRpro showed the least dispersion of mutation probability estimates with a P value of 0.205, compared with 0.034 for PREMM(1,2) and 0.001 for MMRpredict.

We found all three carried out well in a cancer genetics setting, with PREMM(1,2) giving slightly better estimates. There were some significant discrepancies between the models in cases where the proband had endometrial cancer.