ClinVar

Description

Variant summary: CDH1 c.2635G>A (p.Gly879Ser) results in a non-conservative amino acid change located in the cytoplasmic domain (IPR000233) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 277608 control chromosomes, predominantly at a frequency of 0.00025 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2635G>A has been reported in the literature in individuals with suspected Lynch syndrome or affected with lobular breast cancer (Valente_2014, Yurgelun_ 2015) without strong evidence of causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 25067988, 26123647, 28166811, 30311375, 30287823). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=12) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.