Clinical Implication of <i>CDH1</i> Mutations in Genetic Testing for Diffuse Gastric Cancer Patients

<b><i>Introduction:</i></b> The objective of this study was to reclassify published germline <i>CDH1</i> variants identified in gastric cancer (GC) in accordance with the latest <i>ClinVar</i> definition and to correlate their pathogenicity with the established international clinical criteria for genetic testing. <b><i>Methods:</i></b> The relevant literature dating from 1998 to 2019 was systematically searched for data on <i>CDH1</i> germline mutations in accord with PRISMA guidelines. The collected variants were classified according to the latest <i>ClinVar</i> definition into the following classes: benign (B), likely benign (LB), pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS). The McNemar test was used to compare the adequacy of current versus previous International GC Linkage Consortium (IGCLC) criteria. <b><i>Results:</i></b> We reclassified a total of 247 <i>CDH1</i> variants, and we identified that about 70% of B/LB variant carriers were not fulfilling the defined clinical criteria. Instead, all P/LP variants (100%) were associated with the hereditary diffuse gastric cancer (HDGC) phenotype fulfilling the 2020 ILGCC criteria, with a significant improvement (<i>p</i> = 0.025) compared to previous version. <b><i>Conclusions:</i></b> We conclude that germline <i>CDH1</i> genetic testing is indicated only in families meeting the clinical criteria for the HDGC syndrome. This observation suggests that clinical phenotypes that do not clearly fulfill these criteria should not be considered for <i>CDH1</i> genetic testing.