Summary
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.
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Abbreviations
- ESE:
-
exonic splicing enhancer
- HGVS:
-
Human Genome Variation Society
- OMIM:
-
Online Mendelian Inheritance in Man
- LSDB:
-
Locus Specific Data Base
- UTR:
-
untranslated region
References
Mazoyer, S., Dunning, A. M., Serova, O., Dearden, J., Puget, N., Healey, C. S., et al. (1996) A polymorphic STOP in BRCA2. Nat. Genet. 14, 253–254.
Liu, W., Qian, C., and Francke, U. (1997) Silent mutation induces exon skipping of fibrillin-1 gene in Marfan syndrome. Nat. Genet. 6, 328–329.
Claustres, M., Horaitis, O., Vanevski, M., and Cotton, R. G. (2002) Time for a unified system of mutation description and reporting: a review of locus-specific mutation databases. Genome Res. 12, 680–688.
Horaitis, O., and Cotton, R. G. (2004) The challenge of documenting mutation across the genome: the human genome variation society approach. Hum. Mutat. 23, 447–452.
Lane, T. F., Lin, C., Brown, M. A, Solomon, E., and Leder, P. (2000) Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice. Oncogene 19, 4085–4090.
Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., De Die-Smulders, C., et al. (2002) Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609.
Goldgar, D. E., Easton, D. F., Deffenbaugh, A. M., Monteiro, A. N., Tavtigian, S. V., Couch, F. J., et al. (2004) Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am. J. Hum. Genet. 75, 535–544.
Harvey, J. S., Carey, W. F., and Morris, C. P. (1998) Importance of the glycosylation and polyadenylation variants in metachromatic leukodystrophy pseudodeficiency phenotype. Hum. Mol. Genet. 7, 1215–1219.
Altschul, S. F., Gish, W., Miller, W., Myers, E. W., and Lipman, D. J. (1990) Basic local alignment search tool. J. Mol. Biol. 215, 403–410.
Abkevich, V., Zharkikh, A., Deffenbaugh, A. M., Frank, D., Chen, Y., Shattuck D., et al. (2004) Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J. Med. Genet. 41, 492–507.
Grantham, R. (1974) Amino acid difference formula to help explain protein evolution. Science 185, 862–864.
Tavtigian, S. V., Deffenbaugh, A. M., Yin, L., Judkins, T., Scholl, T., Samollow, P. B., et al. (2006) Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J. Med. Genet. 43, 295–305.
Levy-Lahad, E., Catane, R., Eisenberg, S., Kaufman, B., Hornreich, G., Lishinsky, E., et al. (1997) Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast–ovarian cancer families. Am. J. Hum. Genet. 60, 1013–1020.
Roa, B. B., Boyd, A. A., Volcik, K., and Richards, C. S. (1996) Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat. Genet. 14, 185–187.
Thompson, D., Easton, D. F., and Goldgar, D. E. (2003) A full-likelihood method for the valuation of causality of sequence variants from family data. Am. J. Hum. Genet. 73, 652–655.
Lathrop, G. M., Lalouel, J. -M., Julier, C., and Ott, J. (1984) Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. U S A 81, 3443–3446.
Chenevix-Trench, G., Healey, S., Lakhani, S., Waring, P., Cummings, M., Brinkworth, R., et al. (2006) kConFab Investigators. Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res. 66, 2019–2027.
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© 2008 Humana Press, a part of Springer Science+Business Media, LLC
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Grist, S.A., Dubowsky, A., Suthers, G. (2008). Evaluating DNA Sequence Variants of Unknown Biological Significance. In: Trent, R.J. (eds) Clinical Bioinformatics. Methods in Molecular Medicine™, vol 141. Humana Press. https://doi.org/10.1007/978-1-60327-148-6_11
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DOI: https://doi.org/10.1007/978-1-60327-148-6_11
Publisher Name: Humana Press
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