Purpose: To develop a simple scoring system for the likelihood of identifying a BRCA1 or BRCA2 mutation. Methods: DNA samples from affected subjects from 422 non-Jewish families with a history of breast and/ or ovarian cancer were screened for BRCA1 mutations and a subset of 318 was screened for BRCA2 by whole gene screening techniques. Using a combination of results from screening and the family history of mutation negative and positive kindreds, a simple scoring system (Manchester scoring system) was devised to predict pathogenic mutations and particularly to discriminate at the 10% likelihood level. A second separate dataset of 192 samples was subsequently used to test the model's predictive value. This was further validated on a third set of 258 samples and compared against existing models. Results: The scoring system includes a cut-off at 10 points for each gene. This equates to .10% probability of a pathogenic mutation in BRCA1 and BRCA2 individually. The Manchester scoring system had the best trade-off between sensitivity and specificity at 10% prediction for the presence of mutations as shown by its highest C-statistic and was far superior to BRCAPRO. Conclusion:The scoring system is useful in identifying mutations particularly in BRCA2. The algorithm may need modifying to include pathological data when calculating whether to screen for BRCA1 mutations. It is considerably less time-consuming for clinicians than using computer models and if implemented routinely in clinical practice will aid in selecting families most suitable for DNA sampling for diagnostic testing.T he prevalence of BRCA1 and BRCA2 mutations in families with breast/ovarian cancer depends on the type of cancer found in the families, the number of cases in a family, the age at onset, and the ethnic background. The Breast Cancer Linkage Consortium (BCLC) has carried out analysis in high risk families to ascertain the proportion of familial breast cancers attributable to BRCA1 or BRCA2, or neither.1 In 237 families with at least four cases of breast cancer diagnosed at ,60 years of age (or one or more cases of male breast cancer (MBC) or ovarian cancer contributing to four or more cancers in total) 52% were linked to BRCA1 and 32% to BRCA2, with 16% linked to neither. Of the breast-ovarian families, 81% were linked to BRCA1 and 14% were linked to BRCA2. However, 76% of families with MBC but no ovarian cancer were linked to BRCA2. Of families with four or five cases of female breast cancer only, 67% were not linked to BRCA1 or BRCA2, suggesting the presence of other breast cancer predisposing genes. From this information, it is therefore substantially less likely that families with only female breast cancer cases will harbour BRCA1/2 mutations.

64 families with a history of male breast cancer aged 60 or less or with a family history of male and female breast cancer were screened for the presence of BRCA1 and BRCA2 mutations. Seventeen pathogenic BRCA2 and four BRCA1 mutations were identified (34%) in samples from an affected family member. All but one of the mutations segregated with disease where samples were available and pedigree structure permitted. Despite high sensitivity of mutation testing only 64% of families fulfilling BCLC criteria had an identifiable pathogenic mutation. It is possible that at least some of these families may have mutations in other genes, although we found no involvement of CHEK2 1100delC.

Consistent with prior reports, we observed an increased risk of lung cancer mortality associated with asthma among nonsmokers without a history of cancer.

While there are many reports in the literature of mutation testing of BRCA1 and BRCA2 in breast/ovarian cancer families, the question of which type of ovarian cancers are relevant still pertains. We have undertaken whole gene screening including multiple ligation-dependent probe amplification in an affected individual within 442 unrelated non-Jewish families containing at least one reported ovarian cancer diagnosed less than 50 years or at any age with family history of breast or ovarian cancer for mutations in BRCA1 and BRCA2. A total of 166 mutations were identified 110 (25%) in BRCA1 and 56 (13%) in BRCA2. In families without confirmation of ovarian diagnosis, the detection rate drops significantly. In families fulfilling Breast Cancer Linkage Consortium (BCLC) criteria with confirmed ovarian cancer cases, the mutation detection frequency was 80%. If only BCLC families with unconfirmed ovarian cancers were included, the detection rate dropped to 36% when a relevant ovarian cancer diagnosis was not confirmed. In BCLC families containing only one ovarian cancer, BRCA2 accounted for 45% of identified mutations. No mutations were identified in affected individuals with borderline or mucinous tumours. Detection rates dropped below the 10/20% international thresholds in a number of families with unconfirmed ovarian cancers. Borderline/mucinous pathology substantially reduces the likelihood of identifying a BRCA1/2 mutation. Strenuous efforts should be made to confirm ovarian pathology if the lack of confirmation or refuting the diagnosis would decrease a family's likelihood of mutation detection below screening thresholds. In the UK, a higher proportion of families harbour BRCA2 pathogenic mutations than predicted from previous studies.