Assessing Genetic Variants of Uncertain Significance: The Example of Breast Cancer


Mutations in the BRCA1 or 2 genes can lead to an inherited increased risk of breast, ovarian and other cancers. Molecularly, these mutations manifest primarily as frameshift or nonsense mutations, leading to prematurely truncated proteins that would otherwise function as tumour suppressors. Up to 10–20% of all BRCA mutations are reported as variants of uncertain significance (VUS); these manifest as missense mutations (with resultant amino acid substitution), intronic variants with resultant effect on splicing capacity or in‐frame deletions and insertions, which may or may not change the reading frame of a gene. These variant sequences can confound rather than guide the risk assessment process in the genetic counselling of patients and family members, whether afflicted or not with an actual cancer. Several molecular methods are now able to discriminate those as yet unclassified variants between high and low risk for cancer development; databases have been generated accordingly and may allow some further prediction of the probability of deleterious behaviour.

This article aims to clarify the clinical relevance of BRCA VUS, to assimilate resources and make suggestions for estimating their clinical impact, and to highlight the need for further studies in this area.

Key Concepts:

  • There are limited guidelines for the specific management and surveillance of patients and their family members who harbour genetic variants of uncertain significance.

  • Integrated models to discriminate high‐risk from low‐risk variants have been generated.

  • Application of these models is considered.

  • Further clinical trials for risk management are advocated.

  • Up to 20% of BRCA 1 and 2 mutations can be missense mutations which amount to variants of uncertain significance, the deleterious nature of which are unclear in clinical practice.

Keywords: BRCA; genetic variants; genetic counselling; VUS; BRCA 1; BRCA 2

Figure 1.

A schema of multifaceted determination of classification of BRCA VUSs by contribution of multiple molecular methods approach to use for BRCA‐VUS clinical classification. Reproduced from Calo et al., Figure 1, p. 1653, with permission from Cancers (Open Access journal). © Creative Commons Attribution Licence.

Figure 2.

Flow model representing methods that contribute to estimation of classes of risk of clinical impact of BRCA VUSs (Calo et al., ). Literature suggests to then counsel as if no mutation was detected for Class 1 and 2 and not to use the information as predictive testing in at‐risk relatives; for Class 3, to counsel on the basis of family history and other risk factors but not to use this classification as predictive testing in high‐risk relatives; and to engage full high‐risk surveillance for Class 4 and 5 and to test at‐risk relatives for the variant (Lindor et al., ). Reproduced from Calo et al., Figure 2, p. 1654, with permission from Cancers (Open Access journal). © Creative Commons Attribution Licence.



American Cancer Society (2013) Cancer facts and figures.‐036845.pdf.

Bleicher RJ (2013) Variants of Angelina significance. Breast cancer surgery: May 24 commentary, cancer conversations: hearts and minds united against cancer.

Calo V , Bruno L , La Paglia L et al. (2010) The clinical significance of unknown sequence variants in BRCA genes. Cancers 2: 1644–1660; doi:10.3390/cancers2031644.

Clinical Trials PDQ (2012) COsegregation of VARiants in the BRCA1/2 Genes. IC2011‐11;NCT01689584; COVAR Project. (accessed on 30 July 2013).

Domchek SM and Greenberg RA (2009) Breast cancer gene variants: separating the harmful from the harmless. Journal of Clinical Investigation 119(10): 2895–2897. doi:10.1172/JCI40577.

Domechek S and Weber BL (2008) Genetic variants of uncertain significance: flies in the ointment. Journal of Clinical Oncology 26(10): 16–17.

Frank TS , Deffenbaugh AM , Reid JE et al. (2002) Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. Journal of Clinical Oncology 20(6): 1480–1490.

Goldgar DE , Easton DR , Byrnes GB et al. (2008) Genetic evidence and integration of various data sources for classifying uncertain variants into a single model. Human Mutation 29: 1265–1272.

Goldgar DE , Easton DF , Deffenebaugh AM et al. (2004) Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. American Journal of Human Genetics 75(4): 535–544.

Gomez‐Garcia EB , Oosterwijk JC , Timmernans M et al. (2009) A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history. Breast Cancer Research 11(1): R8. doi:10.1186/bcr2223.

Granader EJ , Dwamena B and Carlos RC (2008) MRI and mammography surveillance of women at increased risk for breast cancer: recommendations using an evidence‐based approach. Academic Radiology 15: 1590–1595.

Hall MJ , Reid JE , Burbidge LA et al. (2009) BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast‐ovarian cancer. Cancer 115(10): 2222–2233.

Karchin R , Agarwal M , Sali A et al. (2008) Classifying variants of undetermined significance in BRCA2 with protein likelihood ratios. Cancer Informatics 6: 203–216.

Lakhani SR , Gusterson BA , Jacquemier J et al. (2000) The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in brca1 or brca2. Clinical Cancer Research 6: 782–789.

Lakhani SR , Reis‐Filho JS , Fulford L et al. (2005) Prediction of brca1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clinical Cancer Research 11: 5175–5180.

Lindor NM , Friedman S , Guidugli L et al. (2012) Progress in clinical interpretation of DNA variants of uncertain significance in BRCA1 and BRCA2. Mayo Clinic Progress. (accessed on 30 July 2013).

Lindor NM , Goldgar DE , Tavtigian SV et al. (2013) BRCA 1/2 sequence of variants of uncertain significance: a primer for providers to assist in discussions and in medical management. Oncologist 18: 1–7.

Metcalfe KA , Finch A , Poll A et al. (2009) Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a brca1 or brca2 mutation. British Journal of Cancer 100: 421–425.

Miller‐Samuel S , MacDonald DJ , Weitzel JN et al. (2011a) Variants of uncertain significance in breast cancer‐related genes: real‐world implications for a clinical conundrum. Part one: clinical genetics recommendations. Current Clinical Practice – Seminars in Oncology 38(4): 469–480.

Miller‐Samuel S , Rosenberg A , Berger A et al. (2011b) BRCA1 and BRCA2 variants of uncertain significance. Part two: medical management. Current Clinical Practice – Seminars in Oncology 38(5): 605–611.

Moghadasi S , Hofland J , Wouts JN et al. (2013) Variants of uncertain significance in BRCA1 and BRCA2 assessment of in‐silico analysis and a proposal for communication in genetic counseling. Journal of Medical Genetics 50(2): 74–79.

Murray ML , Cerrato F , Bennett RL and Jarvik GP (2011) Follow‐up of carriers of BRCA1 and BRCA2 variants of unknown significance: variant reclassification and surgical decisions. Genetics in Medicine 13(12): 998–1005.

NCCN Guidelines in Clinical Practice (2013) Hereditary breast and/or ovarian cancer syndrome, version 3.

Plon SE , Eccles DM , Easton D et al. (2008) IARC unclassified genetic variants working group. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Human Mutation 29(11): 1282–1291.

Radice P , De Summa S , Caleca L et al. (2011) Unclassified variants in BRCA genes: guidelines for interpretation. Annals of Oncology 1(22 suppl. 1): I18–I23. doi:10.1093/annonc/mdq661

Ready KJ , Gutierrez‐Barrera AM , Atchley D et al. (2011) Cancer risk management decisions of women with BRCA variants of uncertain significance. The Breast Journal 17(2): 210–212.

Roussi P , Sherman KA , Miller S et al. (2009) Enhanced counselling for women undergoing brca1/2 testing: impact on knowledge and psychological distress – results from a randomised clinical trial. Psychology and Health 25: 401–415.

Sawyer S , Mitchell G , McKinley J et al. (2012) A role for common genetic variants in the assessment of familial breast cancer. Journal of Clinical Oncology 30(35): 4330–4336.

Spearman AD , Sweet K , Zhou X‐P et al. (2008) Clinical applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. Journal of Clinical Oncology 26: 5393–5400.

Sweet K , Senter L , Pilarski R et al. (2010) Characterization of BRCA1 ring finger variants of uncertain significance. Breast Cancer Research and Treatment 119: 737–743.

Further Reading

Chang S , Biswas K , Martin BK et al. (2009) Expression of human BRCA1 variants in mouse ES cells allows functional analysis of BRCA1 mutations. Journal of Clinical Investigation 119: 3160–3171.

Hofstra RM , Spurdle AB , Eccles D et al. (2008) Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance. Human Mutation 29: 1292–1303.

Lee MS , Green R , Marsillac SM et al. (2010) Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Research 70: 4880–4890.

Lindor NM , Guidugli L , Wang X et al. (2012) A review of a multifactorial probability‐based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Human Mutation 33(1): 8–21.

Millot GA , Carvalho MA , Caputo SM et al. (2012) ENIGMA Consortium Functional Assay Working Group. A guide for functional analysis of BRCA1 variants of uncertain significance. Human Mutation 33: 1526–1537.

Thomassen M , Blanco A , Montagna M et al. (2012) Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members. Breast Cancer Research and Treatment 132: 1009–1023.

Walker LC , Whitney PJ , Couch FJ et al. (2010) Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: implications for prediction of pathogenicity. Human Mutation 31: e1484–e1505.

Whiley PJ , Guidugli L , Walker LC et al. (2011) Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary. Human Mutation 32: 678–687.

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Morris, Gloria J(Dec 2013) Assessing Genetic Variants of Uncertain Significance: The Example of Breast Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025220]