The MGRB samples were significantly depleted for rare pathogenic variation in the APC, MLH1, MSH2, MSH6, PMS2, and SMAD4 genes, relative to colorectal cancer cases (Fig. 1a, 1 of 717 MGRB with pathogenic variants, vs 2 of 40 cancer cases, odds ratio 0.027, 95% CI 0.001–0.53, two-sided p = 0.008, n = 757, Fisher’s exact test). This evidence concerns the gene SMAD4 and cancer.