BRCA1/2 sequence variants of uncertain significance: A primer for providers to assist in discussions and in medical management

Oncologist

Volumn 18, Issue 5, 2013, Pages 518-524

  Lindor, Noralane M ^a   Goldgar, David E ^b   Tavtigian, Sean V ^b   Plon, Sharon E ^c   Couch, Fergus J ^d  

^a MAYO CLINIC   (United States)

^b UNIVERSITY OF UTAH   (United States)

^c BAYLOR COLLEGE OF MEDICINE   (United States)

^d MAYO CLINIC   (United States)

Author keywords

BRCA1; BRCA2; Counseling; Likelihood; Management; Multifactorial

Indexed keywords

BRCA1 PROTEIN; BRCA2 PROTEIN; PROTEIN VARIANT;

ARTICLE; BRCA GENE; BREAST CANCER; CANCER SUSCEPTIBILITY; DECISION MAKING; DISEASE ASSOCIATION; DNA REPAIR; DNA SEQUENCE; GENE; GENE MUTATION; GENE SEQUENCE; GENETIC DISORDER; GENETIC SCREENING; HUMAN; OVARY CANCER; PATHOGENICITY; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN EXPRESSION; PUBLICATION; SCORING SYSTEM; SEGREGATION ANALYSIS; SENSITIVITY AND SPECIFICITY;

BRCA1; BRCA2; COUNSELING; LIKELIHOOD; MANAGEMENT; MULTIFACTORIAL;

BRCA1 PROTEIN; BRCA2 PROTEIN; BREAST NEOPLASMS; FEMALE; GENETIC PREDISPOSITION TO DISEASE; GENETIC TESTING; GENETIC VARIATION; HUMANS; LIKELIHOOD FUNCTIONS; MIDDLE AGED; MODELS, STATISTICAL; MUTATION; OVARIAN NEOPLASMS; PROBABILITY; SEQUENCE ANALYSIS, DNA;

EID: 84878212439     PISSN: 10837159     EISSN: 1549490X     Source Type: Journal    
DOI: 10.1634/theoncologist.2012-0452     Document Type: Article

References (50)

1. Ready K, Gutierrez-Barrera AM, Amos C et al. Cancer risk management decisions of women with BRCA1 or BRCA2 variants of uncertain significance. Breast J 2011;17:210-212.
2. Lindor NM, Guidugli L, Wang X et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat 2012;33:8-21.
3. Richards CS, Bale S, Bellissimo DB et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10:294-300.
4. Goldgar DE, Easton DF, Deffenbaugh AM et al. Integrated evaluation of DNA sequence variants of unknownclinical significance: Application to BRCA1 and BRCA2.AmJ Hum Genet 2004;75:535-544.
5. Tavtigian SV, Greenblatt MS, Goldgar DE et al. Assessing pathogenicity: Overview of results from the IARC Unclassified Genetic Variants Working Group. Hum Mutat 2008;29:1261-1264.
6. Tavtigian SV, Byrnes GB, Goldgar DE et al. Classification of rare missense substitutions, using risk surfaces, with genetic-and molecular-epidemiology applications. Hum Mutat 2008;29:1342-1354.
7. Tavtigian SV, Deffenbaugh AM, Yin L et al. Comprehensive statistical study of 452 BRCA1 missense substitutionswithclassificationofeightrecurrentsubstitutions as neutral. JMedGenet 2006;43:295-305.
8. Plon SE, Eccles DM, Easton D et al. Sequencevariant classification and reporting: Recommendations for improving the interpretation of cancer susceptibility genetic test results.HumMutat 2008; 29:1282-1291.
9. Nanda R, Schumm LP, Cummings S et al. Genetic testing in an ethnically diverse cohort of high-risk women: A comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. JAMA 2005;294:1925-1933.
10. Kurian AW. BRCA1 and BRCA2 mutations across race and ethnicity: Distribution and clinical implications. Curr Opin Obstet Gynecol 2010;22:72-78.
11. Haffty BG, Silber A, Matloff E et al. Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women. J Med Genet 2006;43:133-137.
12. Thompson D, Easton DF, Goldgar DE. A fulllikelihood method for the evaluation of causality of sequence variants from family data. Am J Hum Genet 2003;73:652-655.
13. Mohammadi L, Vreeswijk MP, Oldenburg R et al. A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2asanexample. BMCCancer 2009; 9:211.
14. Easton DF, Deffenbaugh AM, Pruss D et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. AmJ Hum Genet 2007;81:873-883.
15. Spurdle AB, Healey S, Devereau A et al. ENIGMA-evidence-based network for the interpretation of germline mutant alleles: An international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum Mutat 2012;33:2-7.
16. Spurdle AB, Whiley PJ, Thompson B et al. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk. J Med Genet 2012;49:525-532.
17. Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res 2001;11: 863-874.
18. Ramensky V, Bork P, Sunyaev S. Human nonsynonymous SNPs: Server and survey. Nucleic Acids Res 2002;30:3894-3900.
19. Tavtigian SV, Greenblatt MS, Lesueur F et al. In silico analysis of missense substitutions using sequence-alignment based methods. Hum Mutat 2008;29:1327-1336.
20. Dorfman R, Nalpathamkalam T, Taylor C et al. Docommonin silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? Clin Genet 2010;77:464-473.
21. Hicks S, Wheeler DA, Plon SE et al. Prediction of missense mutation functionality depends on both the algorithm and sequence alignment employed. Hum Mutat 2011;32:661-668.
22. Wu K, Hinson SR, Ohashi A et al. Functional evaluationandcancer risk assessment ofBRCA2unclassified variants. Cancer Res 2005;65:417-426.
23. Lovelock PK, Spurdle AB, Mok MT et al. Identification of BRCA1 missense substitutions that confer partial functional activity: Potential moderate risk variants? Breast Cancer Res 2007;9:R82.
24. Guidugli L, Pankratz VS, Singh N et al. A classification model for BRCA2 DNA binding domain missense variants based on homology directed repair activity. Cancer Res 2013;73:265-275.
25. Spearman AD, Sweet K, Zhou XP et al. Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol 2008;26:5393-5400.
26. Chenevix-Trench G, Healey S, Lakhani S et al. Genetic and histopathologic evaluation of BRCA1 andBRCA2DNAsequence variants ofunknownclinical significance. Cancer Res 2006;66:2019-2027.
27. Goldgar DE, Easton DF, Byrnes GB et al. Genetic evidence and integration of various data sources for classifying uncertain variants into a single model. Hum Mutat 2008;29:1265-1272.
28. Vallee MP, Francy TC, Judkins MK et al. ClassificationofmissensesubstitutionsintheBRCAgenes: AdatabasededicatedtoEx-UVs. HumMutat 2012;33:22-28.
29. Deffenbaugh AM, Frank TS, Hoffman M et al. Characterization of common BRCA1 and BRCA2 variants. Genet Test 2002;6:119-121.
30. Abkevich V, Zharkikh A, DeffenbaughAMet al. Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet 2004;41:492-507.
31. Judkins T, Hendrickson BC, Deffenbaugh AM et al. Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations. Cancer Res 2005;65:10096-10103.
32. Phelan CM, Dapic V, Tice B et al. Classification of BRCA1 missense variants of unknown clinical significance. J Med Genet 2005;42:138-146.
33. Tesoriero AA, Wong EM, Jenkins MA et al. Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families. Hum Mutat 2005;26:495.
34. Bonatti F, Pepe C, TancrediMet al. RNA-based analysis of BRCA1 and BRCA2 gene alterations. Cancer Genet Cytogenet 2006;170:93-101.
35. Carvalho MA, Marsillac SM, Karchin R et al. Determination of cancer risk associated with germ line BRCA1 missense variants by functional analysis. Cancer Res 2007;67:1494-1501.
36. Osorio A, Milne RL, Honrado E et al. Classification of missense variants ofunknownsignificance in BRCA1 based on clinical and tumor information. Hum Mutat 2007;28:477-485.
37. Farrugia DJ, Agarwal MK, Pankratz VS et al. FunctionalassaysforclassificationofBRCA2variantsofuncertain significance. CancerRes 2008;68:3523-3531.
38. Giannini G, Capalbo C, Ottini L et al. Clinical classification of BRCA1 DNA missense variants: H1686Qis a novel pathogenic mutation occurring in the ontogenetically invariant THV motif of the Nterminal BRCT domain. J Clin Oncol 2008; 26: 4212-4214; author reply 4214-4215.
39. Hansen TV, Bisgaard ML, Jonson L et al. Novel de novoBRCA2mutationinapatientwithafamilyhistory of breast cancer. BMCMedGenet 2008;9:58.
40. Malacrida S, Agata S, Callegaro M et al. BRCA1 p.Val1688del is a deleterious mutation that recurs in breast and ovarian cancer families from Northeast Italy. J Clin Oncol 2008; 26:26-31.
41. Spurdle AB, Couch FJ, Hogervorst FB et al. Prediction and assessment of splicing alterations: Implications for clinical testing. HumMutat 2008;29:1304-1313.
42. Caux-Moncoutier V, Pages-Berhouet S, Michaux D et al. Impact of BRCA1 and BRCA2 variants on splicing: Clues from an allelic imbalance study. Eur J Hum Genet 2009;17:1471-1480.
43. Chang S, Biswas K, Martin BK et al. Expression of human BRCA1 variants in mouse ES cells allows functional analysis ofBRCA1mutations. J Clin Invest 2009;119:3160-3171.
44. Lee MS, Green R, Marsillac SM et al. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res 2010;70:4880-4890.
45. Sweet K, Senter L, Pilarski R et al. Characterization of BRCA1 ring finger variants of uncertain significance. Breast Cancer Res Treat 2010;119:737-743.
46. Walker LC, Whiley PJ, Couch FJ et al. Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: Implications for prediction of pathogenicity. Hum Mutat 2010;31:E1484-E1505.
47. Whiley PJ, Pettigrew CA, Brewster BL et al. Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts. BMC Med Genet 2010;11:80.
48. Biswas K, Das R, Alter BP et al. A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay. Blood 2011;118:2430-2442.
49. Whiley PJ, Guidugli L, Walker LC et al. Splicingand multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/ exon boundary. Hum Mutat 2011;32:678-687.
50. Thomassen M, Blanco A, Montagna M et al. Characterization ofBRCA1andBRCA2splicing variants:Acollaborative report by ENIGMA consortium members. BreastCancerResTreat 2012;132:1009-1023.