Establishing a control population to screen for the occurrence of nineteen unclassified variants in the BRCA1 gene by denaturing high-performance liquid chromatography.

Abstract Numerous missense mutations in BRCA1 and BRCA2 are detected during clinical screening of breast and ovarian cancer patients. Because of the lack of a functional protein assay to determine the functional consequence of these mutations, patients are often frustrated by inconclusive results due to unclassified variants (UV). To determine whether a reported UV is also present in a control collective and therefore more likely be a rare polymorphism than a deleterious mutation, we collected a control population consisting of 95 females and 25 males aged over 60 years (mean 73 years) without a family history of BRCA associated cancers. The age of the control group is beyond the median onset of breast and ovarian cancer with a hereditary background. These controls were analysed for the presence of 19 known UVs in BRCA1 with the DHPLC technique. Only four of the 19 variants (R496H, R866C, S1040N and M1652I) were detected and can be considered polymorphims. However, no firm conclusion can be drawn about the functional relevance of the other 15 variants.