Standard Mutation Nomenclature in Molecular Diagnostics

Abstract

To translate basic research findings into clinical prac-tice , it is essential that information about mutations and variations in the human genome are communi-cated easily and unequivocally. Unfortunately, there has been much confusion regarding the description of genetic sequence variants. This is largely because research articles that first report novel sequence vari-ants do not often use standard nomenclature , and the final genomic sequence is compiled over many sepa-rate entries. In this article , we discuss issues crucial to clear communication , using examples of genes that are commonly assayed in clinical laboratories. Al-though molecular diagnostics is a dynamic field, this should not inhibit the need for and movement toward consensus nomenclature for accurate reporting among laboratories. Our aim is to alert laboratory scientists and other health care professionals to the important issues and provide a foundation for further discussions that will ultimately lead to solutions. (J Mol Diagn 2007, 9:1– 6; DOI: 10.2353/jmoldx.2007.060081) The complexity and inherent variation of the human ge-nome sequence have placed unprecedented demands on bioinformatics resources to assure organized data management. 1 Genomic data are continuously translated into clinical molecular tests, and laboratory reports are generated for patient management and clinical and epi-demiological studies. The consistent use of uniform no-menclature in the management of DNA sequence data is especially critical for concise communication of diagnos-tic testing and genetic risk assessment. Just as stan-dards were established early in the Human Genome Project for uniform documentation and collation of se-quence data, conventions for standardized nomenclature of variant sequences—mutations and polymorphisms— have been developed and promulgated. 2–5 Although in this article we use the term " mutation " to imply a delete-rious genetic sequence variation, our discussion here is relevant to all small genetic sequence variations, whether neutral or deleterious. Despite the nominal acceptance of these standards, clinical mutation testing and screening for major genetic disorders still suffer from the use of nonstandard and variable mutation nomenclature. In fact, colloquial designations for mutations of clinical impor-tance are used so broadly that many geneticists and molecular diagnosticians are probably unaware that they are nonstandard. This may cause confusion when cross-referencing between the original literature and modern databases. In an effort to clarify the nomenclature recommenda-tions of the Human Genome Variation Society (HGVS), we first briefly illustrate how to name a particular sequence variant (either novel or known) using standard nomencla-ture. Recommendations for methods of interpreting se-quence variants, whether deleterious or neutral, have