There is no clear model of how pharmacogenetic tests will be delivered in clinical practice. Patients expect to receive pharmacogenetic services from healthcare professionals who are able to explain the test, and interpret the implications for prescribing, with confidence. The gap between patients' high expectations for information and healthcare professionals' current knowledge and reluctance to deliver pharmacogenetic services highlights the urgent need for better education and training of healthcare professionals in pharmacogenetics.

Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

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BackgroundHuntington’s disease (HD) is caused by an expanded CAG trinucleotide repeat within the Huntingin gene, with affected individuals inheriting >36 CAG repeats. Intermediate alleles (IAs) are classed as 27–35 CAG repeats. Although IAs do not fall within the disease causing range, they are susceptible to paternal germline instability, and so may expand into the reduced penetrance or full mutation range upon transmission to the next generation. There are several factors which are thought to influence CAG repeat instability. However, the risk of IAs expanding into the HD disease causing range has been difficult to establish. Case history and conclusionsWe present two cases, where intermediate alleles have expanded into the full mutation range. The first case describes a family where a paternally inherited intermediate allele of 29 CAG repeats has expanded into a full mutation of 45 CAG repeats. This finding has been confirmed by PCR and linkage analysis and as far as we are aware, this degree of expansion has not been described in the literature before. The second case describes a family where an intermediate allele of 32 has expanded to 44 CAG repeats. We discuss the implications of this both for the family, and the genetic counsellor involved and present some of the challenges associated with genetic counselling for IAs.