1. PERFORMANCE OF DIFFERENT MODELS PREDICTING THE PRE-TEST PROBABILITY OF CARRYING MUTATIONS IN BRCA1 OR BRCA2 IN 330 ITALIAN FAMILIES Silvano Presciuttini, Paolo Aretini, Fabio Marroni, Generoso Bevilacqua, and the Italian Consortium for Hereditary Breast and Ovarian cancer

2. INTRODUCTION The Italian Consortium for Hereditary Breast and Ovarian Cancer has recently established a database of pedigrees analyzed for BRCA1 and/or BRCA2 mutations. We show results of a pilot study on a first set of 330 families collected in four centers. The general project has two main goals:  To validate the use of the program BRCAPRO in calculating probabilities of identifying pathogenic mutations with a large collection of Italian families  To customize the program to the Italian populations by estimating the parameter values that result in the best calibration of the model

3. FAMILIES AND MUTATIONS The mutation identification rate and the BRCA1:BRCA2 rate are clearly different among centers, but this does not introduce a severe bias for our purposes

4. Global comparison BRCAPRO vs. MYRIAD BRCAPRO : (sensitivity of molecular techniques set to 70%) MYRIAD :

5. PROBABILITIES COMPUTED BY BRCAPRO, SEPARATELY FOR BRCA1 AND BRCA2

6. EFFECT OF CHANGING ALLELE FREQUENCIES The default values of mutated allele frequencies in BRCAPRO are 0.0006 and 0.00022 for BRCA1 and BRCA2, respectively The default values of mutated allele frequencies in BRCAPRO are 0.0006 and 0.00022 for BRCA1 and BRCA2, respectively We examined the consequences of changing these values on the observed and expected number of mutations (the source code of BRCAPRO was kindly supplied by G. Parmigiani) We examined the consequences of changing these values on the observed and expected number of mutations (the source code of BRCAPRO was kindly supplied by G. Parmigiani) We used 8 combinations of allele frequencies, and re- calculated the probabilities in all families for each combination We used 8 combinations of allele frequencies, and re- calculated the probabilities in all families for each combination

7. PEARSON CHI SQUARE AS A MEASURE OF GOODNESS OF FIT We computed the Pearson chi square for each combination of allele frequency, summing together the BRCA1 and BRCA2 values (in total, 10 observed-expected contributions). The diagram beside shows these values in the form of relative size of circles (the smaller a circle, the lower the chi square)

8. THE COMBINATION WITH THE LOWEST CHI SQUARE p BRCA1 = 0.0006, p BRCA2 = 0.001 These values are similar to those estimated in recent population- based studies of HBC

9. CONCLUSIONS It is probably possible to improve the observed-expected accordance by further exploring the space of allele frequencies It is probably possible to improve the observed-expected accordance by further exploring the space of allele frequencies However, a substantial improvement can probably be obtained by changing the values of penetrance functions However, a substantial improvement can probably be obtained by changing the values of penetrance functions Coupling the above analyses with additional criteria to stratify the families (e.g., by family profile: HBC, HBOC, HOC) can lead to a full tailoring of the program to the conditions existing in Italy Coupling the above analyses with additional criteria to stratify the families (e.g., by family profile: HBC, HBOC, HOC) can lead to a full tailoring of the program to the conditions existing in Italy