Predicting the Functional Impact of CDH1 Missense Mutations in Hereditary Diffuse Gastric Cancer.

The role of E-cadherin in Hereditary Diffuse Gastric Cancer (HDGC) is unequivocal. Germline alterations in its encoding gene () are causative of HDGC and occur in about 40% of patients. Importantly, while in most cases alterations result in the complete loss of E-cadherin associated with a well-established clinical impact, in about 20% of cases the mutations are of the missense type. The latter are of particular concern in terms of genetic counselling and clinical management, as the effect of the sequence variants in E-cadherin function is not predictable. If a deleterious variant is identified, prophylactic surgery could be recommended. Therefore, over the last few years, intensive research has focused on evaluating the functional consequences of missense variants and in assessing E-cadherin pathogenicity. In that context, our group has contributed to better characterize germline missense variants and is now considered a worldwide reference centre. In this review, we highlight the state of the art methodologies to categorize variants, as neutral or deleterious. This information is subsequently integrated with clinical data for genetic counseling and management of variant carriers.