Human molecular cytogenetics integrates the knowledge on chromosome and genome organization at the molecularand cellular levels in health and disease. Molecular cytogenetic diagnosis is an integral part of current genomicmedicine and is the standard of care in medical genetics and cytogenetics, reproductive medicine, pediatrics, neuropsychiatryand oncology. Regardless numerous advances in this field made throughout the last two decades, researchers andpractitioners who apply molecular cytogenetic techniques may encounter several problems that are extremely difficult tosolve. One of them is undoubtedly the occurrence of somatic genome and chromosome variations, leading to genomic andchromosomal mosaicism, which are related but not limited to technological and evaluative limitations as well as multiplicityof interpretations. More dramatically, current biomedical literature almost lacks descriptions, guidelines or solutions ofthese problems. The present article overviews all these problems and gathers those exclusive data acquired from studies ofgenome and chromosome instability that is relevant to identification and interpretations of this fairly common cause ofsomatic genomic variations and chromosomal mosaicism. Although the way to define pathogenic value of all the intercellularvariations of the human genome is far from being completely understood, it is possible to propose recommendationson molecular cytogenetic diagnosis and management of somatic genome variations in clinical population.