RT Journal Article SR Electronic T1 First estimates of diffuse gastric cancer risks for carriers of CTNNA1 germline pathogenic variants JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 1189 OP 1195 DO 10.1136/jmg-2022-108740 VO 59 IS 12 A1 Coudert, Marie A1 Drouet, Youenn A1 Delhomelle, Hélène A1 Svrcek, Magali A1 Benusiglio, Patrick R A1 Coulet, Florence A1 Clark, Dana Farengo A1 Katona, Bryson W A1 van Hest, Liselotte P A1 van der Kolk, Lizet E A1 Cats, Annemieke A1 van Dieren, Jolanda M A1 Nehoray, Bita A1 Slavin, Thomas A1 Spier, Isabel A1 Hüneburg, Robert A1 Lobo, Silvana A1 Oliveira, Carla A1 Boussemart, Lise A1 Masson, Laure A1 Chiesa, Jean A1 Schwartz, Mathias A1 Buecher, Bruno A1 Golmard, Lisa A1 Bouvier, Anne-Marie A1 Bonadona, Valérie A1 Stoppa-lyonnet, Dominique A1 Lasset, Christine A1 Colas, Chrystelle YR 2022 UL http://jmg.bmj.com/content/59/12/1189.abstract AB Background Pathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline CTNNA1 PV.Methods Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A ‘leave-one-out’ strategy was used to evaluate estimate uncertainty.Results Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of CTNNA1 PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL.Conclusion This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels.Data are available on reasonable request.