Genetic testing for mutations in cancer susceptibility genes began in the early 1990 s and is now commonly performed [Frank et al., 2002; Lynch et al., 2007]. Important decisions regarding management of cancer susceptibility syndromes are made based on whether an individual carries a pathogenic variant or not. In addition to mutations that are highly likely to cause disease (deletions and truncations), mutation screening often finds missense substitutions, potential splicing variants, and/or small in-frame insertion-deletions that are of uncertain significance (often reported as unclassified variants [UVs] or [VUSs]). It was recognized early, and has come to pass, that unclassified missense substitutions would be a potentially serious problem unless functional assays or other discriminating tests could be established [Castilla et al., 1994]. For example, until recently, up to 12% of BRCA1 and BRCA2 test results reported a UV in the absence of any clearly pathogenic variant [Frank et al., 2002].
Over the last several years, research groups focused on individual diseases have begun to tackle this problem. However, to date, there has been little cross-fertilization. To foster cross-talk among gene-specific groups, and to organize and advance the field, the International Agency for Research on Cancer (IARC; the cancer research branch of the World Health Organization) convened a Working Group on Unclassified Sequence Variants in high-risk cancer susceptibility genes. The group met on February 4 and 5, 2008 and included investigators with specialties ranging from clinical cancer genetics to development of functional assays for susceptibility gene mutations (Table 1). The Working Group’s goals were to establish standards for the approach to classification, including the terminology, evaluation, and validation of data types used in classification. This Special Issue of Human Mutation reports the discussions and recommendations of the Working Group in a series of seven articles. Three additional articles with related content are also presented.