Table 1

Summary of existing risk prediction models for mismatch repair (MMR) gene mutations

Leiden69Amsterdam-plus70Amsterdam-alternative70AIFEG75MMRpro71MMRpredict74PREMM1,272PREMM1,2,673Myriad76
Year published19982004200420062006200620062011–
CRC affected/unaffectedBoth affected and unaffectedBoth affected and unaffectedBoth affected and unaffectedBoth affected and unaffectedBoth affected and unaffectedAffected onlyBoth affected and unaffectedBoth affected and unaffectedAffected only
GenesMLH1, MSH2MLH1, MSH2, MSH6MLH1, MSH2, MSH6MLH1, MSH2MLH1, MSH2, MSH6MLH1, MSH2, MSH6MLH1, MSH2MLH1, MSH2, MSH6MLH1, MSH2
Development dataset184 CRC cases from 184 families;
47 (26%) mutation carriers (28 MLH1, 19 MSH2)		250 families recruited from family cancer clinics; 34 (14%) mutation carriers (25 MLH1, 8 MSH2, 1 MSH6)250 families recruited from family cancer clinics; 34 (14%) mutation carriers (25 MLH1, 8 MSH2, 1 MSH6)Literature review: published estimates of mutation frequencies and cancer penetrances in carriers and non-carriersLiterature review: meta-analyses of mutation frequencies and cancer penetrances and predictive value of MSI test870 CRC cases diagnosed age <55 years, recruited regardless of family history;
38 (4%) mutation carriers (15 MLH1, 16 MSH2, 7 MSH6)		898 individuals (536 affected with CRC) with a personal or family history of Lynch syndrome;
130 (15%) mutation carriers (58 MLH1, 72 MSH2)		4539 individuals (2526 affected with CRC) with a personal or family history of Lynch syndrome;
525 (12%) mutation carriers (204 MLH1, 250 MSH2, 71 MSH6)		3410 individuals
No further details given
Development methodMultivariable logistic regressionMultivariable logistic regressionMultivariable logistic regressionApplication of the Mendelian lawsApplication of the Bayes’ rule and Mendelian lawsMultivariable logistic regressionMultivariable logistic regressionMultivariable logistic regressionNot stated
Input▸ Fulfilment of AC-II (yes/no) ▸ Mean age at diagnosis of CRC of affected relatives ▸ EC in family members (yes/no)▸ Fulfilment of AC-II (yes/no) ▸ Number of relatives with CRC ▸ Number of relatives with >1 CRC and/or EC ▸ Number of relatives with EC ▸ Mean age at diagnosis of CRC and EC of affected relatives ▸ Number of relatives with >5 adenomas▸ Number of relatives with CRC ▸ Number of relatives with >1 CRC and/or EC ▸ Number of relatives with EC ▸ Mean age at diagnosis of CRC and EC of affected relatives ▸ Number of relatives with >5 adenomasFor the counselee and each relative:▸ Exact relation to the counselee ▸ CRC (yes, no) ▸ Age at diagnosis of CRC if affected (<45, 45–60, >60 years) ▸ EC (yes, no) ▸ Result of MSI testing (instability present or not present) if tumour availableFor the counselee and each FDR or SDR: ▸ Exact relation to the counselee ▸ Type of cancer ▸ Age at diagnosis (years) if affected ▸ Current age or age at death or last follow-up (years) if unaffected ▸ Result of MSI (instability present or not) or IHC (loss of expression or present) if tumour available ▸ Result of previous germline testing (positive or negative)For the counselee:▸ Age at diagnosis (years) ▸ Sex ▸ Tumour location (proximal, distal) ▸ Synchronous and/or metachronous (yes, no)
For FDR: ▸ CRC (yes, no) ▸ Youngest age at diagnosis of CRC if affected (<50 or ≥50 years) ▸ EC (yes, no)		For the counselee: ▸ CRC (none, one, ≥2); age at diagnosis if one, youngest age at diagnosis if ≥2 ▸ Colonic adenoma (yes, no); youngest age at diagnosis if affected ▸ EC (yes, no); youngest age at diagnosis ▸ HNPCC-associated cancer* (yes, no) For FDR and SDR (only from affected side of family):  ▸ Number of relatives with CRC (none, one, ≥2); Age at diagnosis if one, youngest age at diagnosis if ≥2 ▸ Number of relatives with EC (none, one, ≥2); age at diagnosis if one, youngest age at diagnosis if ≥2 ▸ Any relatives with another HNPCC-associated cancer* (yes, no)For the counselee: ▸ Sex ▸ CRC (none, one, ≥2); age at diagnosis if one, youngest age at diagnosis if ≥2 ▸ EC (yes, no); youngest age at diagnosis ▸ HNPCC-associated cancer* (yes, no)
For FDR and SDR (only from affected side of family): ▸ Number of relatives with CRC (none, one, ≥2); age at diagnosis if one, youngest age at diagnosis if ≥2 ▸ Number of relatives with EC (none, one, ≥2); age at diagnosis if one, youngest age at diagnosis if ≥2 ▸ Any relatives with another HNPCC-associated cancer* (yes, no)		Not required
Gene-specific estimates givenNoNoNoNoYes (MLH1, MSH2 and MSH6)NoNoYes (MLH1, MSH2 and MSH6)No
Prediction levelFamilyFamilyFamilyIndividualIndividualIndividualIndividualIndividualIndividual
Calculation modeFormula (by hand)Formula (by hand)Formula (by hand)Software
(MLINK of the FASTLINK package 99 100)		Software (CancerGene)Web-basedWeb-basedWeb-basedPrevalence table
Source of calculation mode–––AIFEG websiteMMRpro website, CancerGene software websiteMMRpredict websitePREMM1,2 websitePREMM1,2,6 websiteMyriad website