Familial Risk Stratification Across Cancer Syndromes Using Fam3PRO.

Multi-gene Mendelian model estimating, from family history, the probability of carrying a pathogenic variant and future cancer risk.

Fam3PRO is a Mendelian risk prediction methodology designed to build models spanning an arbitrary number of genes and cancers, here parameterised from population-level literature data for 21 genes and 17 cancers. The authors validate it on three independent, multi-ethnic panel cohorts. Fam3PRO provides discrimination and calibration comparable to the syndrome-specific models BRCAPRO and MMRpro for breast-ovarian and Lynch syndrome genes. For the probability of being heterozygous for at least one pathogenic variant among the 21 genes, discrimination reaches 0.64 (95% CI 0.62-0.67) and calibration (observed/expected) 1.13 (95% CI 1.05-1.22) in the combined cohort. At probability thresholds of 2.5% and 5%, Fam3PRO identifies more individuals at high carrier risk than BRCAPRO and MMRpro.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The value is real for clinics seeing mixed family histories that fit no single syndrome: one model covering 21 genes and 17 cancers avoids stacking ill-fitting syndrome-specific scores. Overall discrimination of 0.64 nonetheless remains modest and does not replace clinical judgement; penetrance parameters are moreover drawn from the literature, with the uncertainty that entails for moderate-risk genes. Worth testing in practice on borderline testing indications.

Analysis by Dr Thibaut Benquey