title: A model to infer the pathogenic significance of CDH1 germline missense variants.
abstract: Germline mutations of the E-cadherin gene (CDH1) are involved in the tumorigenesis of hereditary diffuse gastric cancer (HDGC). Recent studies have highlighted the lifesaving potential of total prophylactic gastrectomy for CDH1 germline mutation carriers. In this regard, CDH1 germline mutations of the missense type represent a clinical burden in genetic counseling, as their pathogenic relevance is not straightforward. In this work, we have outlined a possible multivariate approach to infer the significance of such variants. We reviewed all HDGC-associated E-cadherin germline missense mutations reported to date. The information collected included: co-segregation of the mutation within pedigrees, frequency in healthy population control, recurrence in independent families, and functional in vitro and in silico data. We used the neighbor-joining method to group mutations according to the collected information and assessed the robustness of mutation clusters with a bootstrap test. CDH1 germline missense variants were classified according to the parameters defined in the multivariate analysis. This analysis allowed the distribution of the variants into two distinct groups: neutral variants vs mutations. The model described in this study provides an important tool that can ultimately improve the genetic counseling offered to the carriers of the germline CDH1 missense variants.
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Rua Dr Roberto Frias S/N 4200-465, Porto, Portugal. gsuriano@ipatimup.pt
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Suriano
authors.forename: Susana
authors.initials: S
authors.lastname: Seixas
authors.forename: Jorge
authors.initials: J
authors.lastname: Rocha
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
mesh_terms: D000483:Alleles; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D016022:Case-Control Studies; D003198:Computer Simulation; D005091:Exons; D005787:Gene Frequency; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008957:Models, Genetic; D008958:Models, Molecular; D015999:Multivariate Analysis; D020125:Mutation, Missense; D010375:Pedigree; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000235:genetics
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins