Global population-based prevalence of genetic carriers of CDH1-associated hereditary diffuse gastric cancer

CDH1

Loss-of-function variants in the tumour suppressor gene CDH1

Hereditary diffuse gastric cancer is a rare autosomal dominant genetic disorder caused by loss-of-function variants in the tumour suppressor gene CDH1. The authors estimated carrier frequency by genetic ancestry group in 807,162 unrelated individuals from gnomAD v4.1, using on one hand variants classified as pathogenic or likely pathogenic in ClinVar or ClinGen, and on the other rare variants predicted to be deleterious in silico. Of 3,381 CDH1 variants, 137 met the criteria: 47 classified as pathogenic or likely pathogenic and 90 predicted deleterious. Using curated variants only, the carrier frequency is 8.67 per 100,000, highest in non-Finnish Europeans (10.0 per 100,000), with no carriers observed in the Ashkenazi Jewish, Finnish or Middle Eastern groups. Adding in silico-predicted variants raises the estimate to 44.1 per 100,000, highest in the Middle Eastern group (165.0 per 100,000).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The fivefold gap between curated and in silico-predicted variants mainly measures the uncertainty in interpreting CDH1 variants: without clinical data, nothing indicates that predicted deleterious variants confer the same risk. The genotype-first approach avoids clinical ascertainment bias, but gnomAD provides no phenotypes and these frequencies say nothing about penetrance. For a CDH1 variant found incidentally on an exome or genome, they are a reminder that variant classification matters more than mere presence.

Analysis by Dr Thibaut Benquey