A host of familial cancer syndromes have been described in which several members of the same family develop cancer at a young age due to an inherited genetic susceptibility. It has been well established that germline mutations in the DNA sequence of genes that are protective against cancer, including tumour suppressor and DNA repair genes, are the culprit in most familial cases of cancer. Because they are inherited, these germline mutations are present in every cell of the body from conception into adulthood, knocking out one of the two copies of the protective gene. They confer a high risk of cancer development at a young age, although the cancer itself arises when the remaining normally-functioning copy of the gene is knocked out in susceptible tissues due to contributing environmental conditions, taking with it the last remnants of protection it once afforded against cancer. However, for a number of individuals with young-onset cancer, as well as entire families, the inherited defect remains unidentified, which complicates genetic counselling and clinical management of family members. Lynch syndrome is the most common of all family cancer syndromes, in which patients develop a range of cancers, the most frequent of which are colorectal and uterine cancers. Lynch syndrome is usually caused by germline mutations within one of the four genes that encode the mismatch repair system, most commonly MLH1 or MSH2. Loss of protection from the mismatch repair system results in the accumulation of mutations during cell division, and ultimately, cancer ensues. However, in about a third of Lynch syndrome patients, standard genetic screening fails to identify any pathogenic sequence change within the mismatch repair genes that might be responsible for their disease.