title: Evaluating DNA sequence variants of unknown biological significance.
abstract: Increasingly, the molecular genetics laboratory has to assess the biological significance of changes (variants) in a DNA sequence. Using the large genes BRCA1 and BRCA2 as examples, some approaches used to determine the biological significance of DNA variants are described. These include the characterization of the variant through a review of the literature and the various databases to assess if it has previously been described. Potential difficulties with the various databases that are available are described. Other considerations include the co-inheritance of the variant with other DNA changes, and its evolutionary conservation. Determining the possible effect of the variant on protein function is described in terms of the Grantham assessment as well as identifying functional domains. Studies looking at the distribution of the variant in both the population and the family can also help in assessing its significance. Loss of the variant in a tumor sample would imply that it is not deleterious. Ultimately, it is not any single parameter that helps determine the DNA variants biological significance. Usually this requires multiple lines of evidence.
authors.affiliation: Genetic Pathology, Flinders Medical Centre, Bedford Park South Adelaide, Australia.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Grist
authors.forename: Andrew
authors.initials: A
authors.lastname: Dubowsky
authors.forename: Graeme
authors.initials: G
authors.lastname: Suthers
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D014408:Biomarkers, Tumor / Q000145:classification / Q000302:isolation & purification*; D017124:Conserved Sequence; D004252:DNA Mutational Analysis / Q000379:methods; D030541:Databases, Genetic; D019143:Evolution, Molecular; D005190:Family; D006801:Humans; D009154:Mutation / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: D014408:Biomarkers, Tumor