This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Judkins, T. Articles by Scholl, T. Search for Related Content PubMed PubMed Citation Articles by Judkins, T. Articles by Scholl, T.

Application of Embryonic Lethal or Other Obvious Phenotypes to Characterize the Clinical Significance of Genetic Variants Found in Trans with Known Deleterious Mutations

Myriad Genetic Laboratories, Salt Lake City, Utah

Requests for reprints: Thomas Scholl, Myriad Genetic Laboratories, 320 Wakara Way, Salt Lake City, UT 84108. Phone: 801-584-1126; Fax: 801-584-1190; E-mail: tscholl{at}myriad.com.

This work describes an approach to characterize the clinical significance of genetic variants detected during the genetic testing of BRCA1 in patients from hereditary breast/ovarian cancer families. Results from transgenic mice and extensive clinical testing support the hypothesis that biallelic BRCA1 mutations result in embryonic lethality. Therefore, it is reasonable to conclude that variants of uncertain clinical significance found to reside in trans with known deleterious mutations impart reduced risk for cancer. This approach was applied to a large data set of 55,630 patients who underwent clinical BRCA1 screening by whole gene direct DNA sequencing. Fourteen common single nucleotide polymorphisms (SNPs) were used to assign 10 previously defined common, recurrent, or canonical haplotypes in 99% of these cases. From a total of 1,477 genetic variants detected in these patients, excluding haplotype-tagging SNPs, 877 (59%) could be unambiguously assigned to one or more haplotypes. In 41 instances, variants previously classified as being of uncertain clinical significance, mostly missense variants, were excluded as fully penetrant mutations due to their coincidence in trans with known deleterious mutations. From a total of 1,150 patients that harbored these 41 variants, 956 carried one as the sole variant of uncertain clinical significance reported. This approach could have widespread application to other disease genes where compound heterozygous mutations are incompatible with life or result in obvious phenotypes. This largely computational technique is advantageous because it relies upon existing clinical data and is likely to prove informative for prevalent genetic variants in large data sets.

This article has been cited by other articles:

				A. D. Spearman, K. Sweet, X.-P. Zhou, J. McLennan, F. J. Couch, and A. E. Toland Clinically Applicable Models to Characterize BRCA1 and BRCA2 Variants of Uncertain Significance J. Clin. Oncol., November 20, 2008; 26(33): 5393 - 5400. [Abstract] [Full Text] [PDF]

				D. J. Farrugia, M. K. Agarwal, V. S. Pankratz, A. M. Deffenbaugh, D. Pruss, C. Frye, L. Wadum, K. Johnson, J. Mentlick, S. V. Tavtigian, et al. Functional Assays for Classification of BRCA2 Variants of Uncertain Significance Cancer Res., May 1, 2008; 68(9): 3523 - 3531. [Abstract] [Full Text] [PDF]

				A. B. Spurdle, S. R. Lakhani, S. Healey, S. Parry, L. M. Da Silva, R. Brinkworth, J. L. Hopper, M. A. Brown, D. Babikyan, G. Chenevix-Trench, et al. Clinical Classification of BRCA1 and BRCA2 DNA Sequence Variants: The Value of Cytokeratin Profiles and Evolutionary Analysis--A Report From the kConFab Investigators J. Clin. Oncol., April 1, 2008; 26(10): 1657 - 1663. [Abstract] [Full Text] [PDF]

				S. Malacrida, S. Agata, M. Callegaro, C. Casella, D. Barana, M. C. Scaini, S. Manoukian, C. Oliani, P. Radice, M. Barile, et al. BRCA1 p.Val1688del Is a Deleterious Mutation That Recurs in Breast and Ovarian Cancer Families From Northeast Italy J. Clin. Oncol., January 1, 2008; 26(1): 26 - 31. [Abstract] [Full Text] [PDF]

				M. A. Carvalho, S. M. Marsillac, R. Karchin, S. Manoukian, S. Grist, R. F. Swaby, T. P. Urmenyi, E. Rondinelli, R. Silva, L. Gayol, et al. Determination of Cancer Risk Associated with Germ Line BRCA1 Missense Variants by Functional Analysis Cancer Res., February 15, 2007; 67(4): 1494 - 1501. [Abstract] [Full Text] [PDF]

				J. Simard, M. Dumont, A.-M. Moisan, V. Gaborieau, H. Vezina, F. Durocher, J. Chiquette, M. Plante, D. Avard, P. Bessette, et al. Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer J. Med. Genet., February 1, 2007; 44(2): 107 - 121. [Abstract] [Full Text] [PDF]