ClinVar Genomic variation as it relates to human health

The NM_004360.5(CDH1):c.324A>G (p.Arg108=) variant has an allele frequency of 0.00769 (0.769%, 192/24966 alleles) in the African subpopulation and one homozygote in the European (Non-Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2.

Variant summary: Variant Summary: The c.324G>A (p.Arg108=) in CDH1 gene is a synonymous change that involves a non-conserved nucleotide with a prediction of being a "disease-causing" by mutation taster. 3/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at an overall allele frequency of 0.1% (126/121336 chrs tested), mainly in individuals of African descent (0.83%; 86/10384 chrs tested). The observed frequency exceeds the maximum expected allele frequency for a pathogenic CDH1 variant (0.0028%), suggesting that it is a common polymorphism. Based on the published reports, the variant of interest was found in affected individuals as well as in unaffected controls. Lastly, the variant has been reported as Benign by multiple reputable database/clinical laboratories. Taken together, the variant was classified as Benign.

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.

BA1; BS2; BP2_Strong (PMID: 30311375)

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.

CDH1: BP4, BP7, BS1, BS2

The CDH1 p.Arg108= variant was identified in 3 of 594 proband chromosomes (frequency: 0.005) from Canadian and Brazilian individuals or families with early-onset gastric cancer or nonsyndromic orofacial cleft (reportedly associated with gastric cancer), and in 6 of 1218 chromosomes (frequency: 0.005) from healthy individuals (Bacani_2006_16801346, Brito_2015_26123647, ). The variant was also identified in dbSNP (ID: rs116542018) “With Likely benign allele”, ClinVar (classified benign by GeneDx, Invitae and EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), and likely benign by Ambry Genetics), Clinvitae (4x), Insight Colon Cancer Gene Variant Database (2x), and in control databases in 288 (1 homozygous) of 276950 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 187 of 24030 chromosomes (freq: 0.008), Other in 4 of 6462 chromosomes (freq: 0.0006), Latino in 32 of 34418 chromosomes (freq: 0.0009), European Non-Finnish in 43 (1 homozygous) of 126460 chromosomes (freq: 0.0003), East Asian in 1 of 18866 chromosomes (freq: 0.00005), European Finnish in 20 of 25792 chromosomes (freq: 0.0008), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while not observed in the Ashkenazi Jewish population. The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The p.Arg108= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.