Evans DG, Shenton A, Woodward E, Lalloo F, Howell A, Maher ERPenetrance estimates for BRCA1 and BRCA2 based on genetic testing in a clinical cancer genetics service setting. BMC Cancer 8(1): 155

Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital Manchester M13 0JH, UK.
BMC Cancer (Impact Factor: 3.36). 02/2008; 8(1):155. DOI: 10.1186/1471-2407-8-155
Source: PubMed


The identification of a BRCA1 or BRCA2 mutation in familial breast cancer kindreds allows genetic testing of at risk relatives. However, considerable controversy exists regarding the cancer risks in women who test positive for the family mutation.
We reviewed 385 unrelated families (223 with BRCA1 and 162 with BRCA2 mutations) ascertained through two regional cancer genetics services. We estimated the penetrance for both breast and ovarian cancer in female mutation carriers (904 proven mutation carriers - 1442 females in total assumed to carry the mutation) and also assessed the effect on penetrance of mutation position and birth cohort.
Breast cancer penetrance to 70 and to 80 years was 68% (95%CI 64.7-71.3%) and 79.5% (95%CI 75.5-83.5%) respectively for BRCA1 and 75% (95%CI 71.7-78.3%) and 88% (95%CI 85.3-91.7%) for BRCA2. Ovarian cancer risk to 70 and to 80 years was 60% (95%CI 65-71%) and 65% (95%CI 75-84%) for BRCA1 and 30% (95%CI 25.5-34.5%) and 37% (95%CI 31.5-42.5%) for BRCA2. These risks were borne out by a prospective study of cancer in the families and genetic testing of unaffected relatives. We also found evidence of a strong cohort effect with women born after 1940 having a cumulative risk of 22% for breast cancer by 40 years of age compared to 8% in women born before 1930 (p = 0.0005).
In high-risk families, selected in a genetics service setting, women who test positive for the familial BRCA1/BRCA2 mutation are likely to have cumulative breast cancer risks in keeping with the estimates obtained originally from large families. This is particularly true for women born after 1940.

Download full-text


Available from: Anthony Howell,
  • Source
    • "The two most commonly studied breast cancer susceptibility genes are BRCA1 and BRCA2. Mutations in these tumour suppressor genes confer an up to 80–90% lifetime risk of developing breast cancer [12] [13] [14]. These women have a significant CBC risk once diagnosed with breast cancer. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Rates of contralateral risk-reducing mastectomy have increased substantially over the last decade. Surgical oncologists are often in the frontline, dealing with requests for this procedure. This paper reviews the current evidence base regarding contralateral breast cancer, assesses the various risk-reducing strategies, and evaluates the cost-effectiveness of contralateral risk-reducing mastectomy.
    International Journal of Surgical Oncology 01/2015; 2015:ID 901046. DOI:10.1155/2015/901046
  • Source
    • "Inherited BRCA1 inactivating mutations are major determinants of breast and ovarian cancer risk, accounting for 46–68% of cases with a family history of breast cancer cases [1], [2], [3], [4]. Since 1996 genetic testing to identify mutations in BRCA1 and BRCA2 has been offered to women with a family history of breast and ovarian cancer [5], [6]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Germline inactivating variants in BRCA1 lead to a significantly increased risk of breast and ovarian cancers in carriers. While the functional effect of many variants can be inferred from the DNA sequence, determining the effect of missense variants present a significant challenge. A series of biochemical and cell biological assays have been successfully used to explore the impact of these variants on the function of BRCA1, which contribute to assessing their likelihood of pathogenicity. It has been determined that variants that co-localize with structural or functional motifs are more likely to disrupt the stability and function of BRCA1. Here we assess the functional impact of 37 variants chosen to probe the functional impact of variants in phosphorylation sites and in the BRCT domains. In addition, we perform a meta-analysis of 170 unique variants tested by the transcription activation assays in the carboxy-terminal domain of BRCA1 using a recently developed computation model to provide assessment for functional impact and their likelihood of pathogenicity.
    PLoS ONE 05/2014; 9(5):e97766. DOI:10.1371/journal.pone.0097766 · 3.23 Impact Factor
  • Source
    • "Breast cancer is the most frequent malignancy in the western world and even though most cases are sporadic, around 5–10% are believed to be hereditary caused by mutations in predisposing genes [1]. Germline mutations in the breast cancer susceptibility gene, BRCA1 confer an estimated 60–85% and 40–60% lifetime risk of developing breast and ovarian cancer respectively by the age of 70 [2]–[5]. BRCA1 is a tumor suppressor gene located on chromosome 17q21 [6] and encodes a multi-domain protein of 1863 amino acids which is involved in important cellular functions such as in DNA repair, transcription and cell cycle control through the DNA damage response [7]–[12]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The identification of variants of unknown clinical significance (VUS) in the BRCA1 gene complicates genetic counselling and causes additional anxiety to carriers. In silico approaches currently used for VUS pathogenicity assessment are predictive and often produce conflicting data. Furthermore, functional assays are either domain or function specific, thus they do not examine the entire spectrum of BRCA1 functions and interpretation of individual assay results can be misleading. PolyPhen algorithm predicted that the BRCA1 p.Ser36Tyr VUS identified in the Cypriot population was damaging, whereas Align-GVGD predicted that it was possibly of no significance. In addition the BRCA1 p.Ser36Tyr variant was found to be associated with increased risk (OR = 3.47, 95% CI 1.13-10.67, P = 0.02) in a single case-control series of 1174 cases and 1109 controls. We describe a cellular system for examining the function of exogenous full-length BRCA1 and for classifying VUS. We achieved strong protein expression of full-length BRCA1 in transiently transfected HEK293T cells. The p.Ser36Tyr VUS exhibited low protein expression similar to the known pathogenic variant p.Cys61Gly. Co-precipitation analysis further demonstrated that it has a reduced ability to interact with BARD1. Further, co-precipitation analysis of nuclear and cytosolic extracts as well as immunofluorescence studies showed that a high proportion of the p.Ser36Tyr variant is withheld in the cytoplasm contrary to wild type protein. In addition the ability of p.Ser36Tyr to co-localize with conjugated ubiquitin foci in the nuclei of S-phase synchronized cells following genotoxic stress with hydroxyurea is impaired at more pronounced levels than that of the p.Cys61Gly pathogenic variant. The p.Ser36Tyr variant demonstrates abrogated function, and based on epidemiological, genetic, and clinical data we conclude that the p.Ser36Tyr variant is probably associated with a moderate breast cancer risk.
    PLoS ONE 04/2014; 9(4):e93400. DOI:10.1371/journal.pone.0093400 · 3.23 Impact Factor
Show more