When analyzing a patient’s karyotype using classic cytogenetic tools, clinical cytogeneticists frequently face a problem of whether the observed morphological variant of a chromosome is the norm or pathology. Here we present three cases, when the use of additional approaches allowed us to accurately and reliably describe the chromosomal abnormalities and to provide a substantiated medical and genetic prognosis. Translocations were preliminary diagnosed in the first two patients. This opinion was subsequently challenged, as these patients were the carriers of rare variants of normal chromosome polymorphisms (21pstkstkpss and 20cenh+). Thus, these diagnostic measures helped the wife of the first patient to maintain the pregnancy, whereas the second patient was referred for IVF. In the third case, the preliminary diagnosis trisomy of chromosome 22 has not been confirmed. This patient turned out to be a carrier of a supernumerary marker chromosome invdup(15)(q13), which offers a much more favorable medical prognosis.