The results do not exclude the possibility that some of the studied MSH6 mutations, which were functional in the in vitro MMR assay, could still affect biochemical events preceding the MMR function in vivo. Yet, a functional MMR defect, especially in situations where cosegregation of missense mutation and disease phenotype cannot be studied, reliably confirms that cancer susceptibility in a family is linked to a found mutation. The gene discussed is MSH6; the disease is cancer.