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. 2004 Oct;75(4):535-44.
doi: 10.1086/424388. Epub 2004 Aug 2.

Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2

David E Goldgar  1 , Douglas F Easton, Amie M Deffenbaugh, Alvaro N A Monteiro, Sean V Tavtigian, Fergus J Couch; Breast Cancer Information Core (BIC) Steering Committee
Affiliations

Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2

David E Goldgar et al. Am J Hum Genet. 2004 Oct.

Abstract

Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model.

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Figures

Figure 1
Figure 1
Flowchart of the procedure for classification of sequence variants of unknown clinical significance. ER = estrogen receptor status; LR = likelihood ratio.
See this image and copyright information in PMC

References

Electronic-Database Information

    1. Berkeley Drosophila Genome Project, http://www.fruitfly.org/seq_tools/splice.html (for splice-site analysis)
    1. Breast Cancer Information Core (BIC) database, http://research.nhgri.nih.gov/bic/
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for BRCA1 and BRCA2)

References

    1. Abkevich V, Zharkikh A, Deffenbaugh A, Frank D, Chen Y, Shattuck D, Skolnick M, Gutin A, Tavtigian S (2004) Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet 41:492–50710.1136/jmg.2003.015867 - DOI - PMC - PubMed
    1. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72:1117–1130 - PMC - PubMed
    1. Barker DF, Almeida ER, Casey G, Fain PR, Liao SY, Masunaka I, Noble B, Kurosaki T, Anton-Culver H (1996) BRCA1 R841W: a strong candidate for a common mutation with moderate phenotype. Genet Epidemiol 13:595–60410.1002/(SICI)1098-2272(1996)13:6<595::AID-GEPI5>3.3.CO;2-0 - DOI - PubMed
    1. Breast Cancer Linkage Consortium (1997) Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 349:1505–151010.1016/S0140-6736(96)10109-4 - DOI - PubMed
    1. Chen CF, Chen PL, Zhong Q, Sharp ZD, Lee WH (1999) Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51 complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint control. J Biol Chem 274:32931–3293510.1074/jbc.274.46.32931 - DOI - PubMed