ClinVar Genomic variation as it relates to human health

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Variant summary: CDH1 c.84C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.00e-05 within Non-Finnish European control individuals (i.e. 4/57386 control chromosomes) in the gnomAD database, which is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.84C>T in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

The CDH1 c.84C>T; p.Cys28Cys variant (rs587780789), to our knowledge, is not reported in the medical literature but is reported as likely benign in ClinVar (Variation ID: 136070). This variant is found in the general population with an overall allele frequency of 0.003% (4/149530 alleles) in the Genome Aggregation Database. This is a synonymous change, the nucleotide is weakly conserved, and computational algorithms do not predict this variant to impact splicing (Alamut v.2.10). Based on available information, this variant is considered to be likely benign.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.