Abstract: Prognostic and diagnostic methods based on somatic microsatellite variability measurements are described. Somatic microsatellite variability measurements can be used to identify defects in DNA repair pathways in a biological sample and to predict or identify one or more pathologies. The methods may statistically compare somatic microsatellite variability between a sample from a cell line or subject with that of a reference sample with defined pathological characteristics and/or defined lesions in DNA repair pathways. The methods are useful for determining the probability that an individual may develop a pathology, such as a cancer, within a specific time frame, and/or are useful as a diagnostic test. The methods have clinical utility in that somatic variability can be evaluated and/or measured as an indication of the amount of genomic instability (e.g., microsatellite and non-microsatellite/SNP), which can then be used as a clinical diagnostic to make clinical decisions, especially in the area of cancer.