Introduction: The objective of this study was to reclassify published germline CDH1 variants identified in gastric cancer (GC) in accordance with the latest ClinVar definition and to correlate their pathogenicity with the established international clinical criteria for genetic testing. Methods: The relevant literature dating from 1998 to 2019 was systematically searched for data on CDH1 germline mutations in accord with PRISMA guidelines. The collected variants were classified according to the latest ClinVar 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. Results: We reclassified a total of 247 CDH1 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 (p = 0.025) compared to previous version. Conclusions: We conclude that germline CDH1 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 CDH1 genetic testing.

Blair VR, McLeod M, Carneiro F, Coit DG, D’Addario JL, van Dieren JM, et al. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. 2020 Aug;21(8):e386–97.
van der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015 Jun;52(6):361–74.
Hansford S, Kaurah P, Li-Chang H, Woo M, Senz J, Pinheiro H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol. 2015 Apr;1(1):23–32.
Corso G, Corso F, Bellerba F, Carneiro P, Seixas S, Cioffi A, et al. Geographical distribution of E-cadherin germline mutations in the context of diffuse gastric cancer: a systematic review. Cancers. 2021 Mar 12;13(6):1269.
Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998 Mar 26;392(6674):402–5.
Corso G, Figueiredo J, La Vecchia C, Veronesi P, Pravettoni G, Macis D, et al. Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect. J Med Genet. 2018 Jul;55(7):431–41.
Girardi A, Magnoni F, Vicini E, Kouloura A, La Vecchia C, Veronesi P, et al. CDH1 germline mutations in families with hereditary lobular breast cancer. Eur J Cancer Prev. 2022 May 1;31(3):274–8.
Garcia-Pelaez J, Barbosa-Matos R, Lobo S, Dias A, Garrido L, Castedo S, et al. Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes. Lancet Oncol. 2023 Jan;24(1):91–106.
Jones EG. Familial gastric cancer. NZ Med J. 1964 May;63:287–96.
Caldas C, Carneiro F, Lynch HT, Yokota J, Wiesner GL, Powell SM, et al. Familial gastric cancer: overview and guidelines for management. J Med Genet. 1999 Dec;36(12):873–80.
Fitzgerald RC, Hardwick R, Huntsman D, Carneiro F, Guilford P, Blair V, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010 Jul;47(7):436–44.
Lowstuter K, Espenschied CR, Sturgeon D, Ricker C, Karam R, LaDuca H, et al. Unexpected CDH1 mutations identified on multigene panels pose clinical management challenges. JCO Precis Oncol. 2017 Nov;1:1–12.
Roberts ME, Ranola JMO, Marshall ML, Susswein LR, Graceffo S, Bohnert K, et al. Comparison of CDH1 penetrance estimates in clinically ascertained families vs families ascertained for multiple gastric cancers. JAMA Oncol. 2019 Sep 1;5(9):1325–31.
Xicola RM, Li S, Rodriguez N, Reinecke P, Karam R, Speare V, et al. Clinical features and cancer risk in families with pathogenic CDH1 variants irrespective of clinical criteria. J Med Genet. 2019;56(12):838–43.
Hakkaart C, Ellison-Loschmann L, Day R, Sporle A, Koea J, Harawira P, et al. Germline CDH1 mutations are a significant contributor to the high frequency of early-onset diffuse gastric cancer cases in New Zealand Māori. Fam Cancer. 2019 Jan;18(1):83–90.
You do not currently have access to this content.