Background: Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer (HDGC) syndrome. The risk assessment and management of HDGC families that do not carry a CDH1 variant is limited. It is therefore difficult for such families to make informed choices about surveillance and risk reducing surgery. This study aimed to identify new candidate genes for HDGC predisposition in families with no detected pathogenic CDH1 variants (CDH1-NPV). Methods: Whole exome sequencing (WES) was performed on DNA extracted from blood obtained as part of the Familial Gastric Cancer Study. Analysis was performed across 39 individuals (28 affected and 11 unaffected) from 22 CDH1-NPV families that fulfil the international criteria for HDGC. Genes with loss-of-function variants were prioritised using gene interaction analysis to identify clusters of genes that could be involved in HDGC predisposition. Findings: Protein-affecting germline variants were identified in known cancer predisposition genes or lesser studied DNA repair genes in six HDGC families. A frameshift deletion within PALB2 was found in a family with a history of gastric and breast cancer. Two MSH2 variants were identified, one frameshift insertion and one previously described start loss, in unrelated affected individuals. One family was identified with a unique combination of variants in DNA repair genes ATR and NBN. A missense variant and a splice acceptor variant were seen in two unrelated families in DNA repair gene RECQL5. Interpretation: This study supports the role of known cancer predisposition gene PALB2 in the HDGC syndrome. It also puts forward new candidates in relation to HDGC risk within CDH1-NPV families. Funding: This work has been funded and supported by the UK Medical Research Council (MRC)/Sackler programme, the European Union Seventh Framework Program (2007–2013)/European Research Council (310018), the National Institute for Health Research Cambridge Biomedical Research Centre and the Experimental Cancer Medicine Centre and Cancer Research UK.