ClinVar Genomic variation as it relates to human health

The c.1417G>A (p.Val473Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 5 of 152,172 alleles in the gnomAD v3.1.2 population database. However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023)

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Van Marcke et al., 2020); This variant is associated with the following publications: (PMID: 15235021, 22850631, 30239046, 33471991, 32295625)

Variant summary: CDH1 c.1417G>A (p.Val473Ile) results in a conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251488 control chromosomes. The observed variant frequency is above 2 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 benign. To our knowledge, no occurrence of c.1417G>A in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32295625, 30239046). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=8) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.

(BP4_Sup) Additional information missing. According to the ACMG gene specific: CDH1 criteria we chose this criterium: BP4 (supporting benign): Prediction tools mainly predict benign effect on protein function (BP4_sup)

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, BS2

BS2_Supporting (PMID: 30311375)

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

The CDH1 p.Val473Ile variant was not identified in the literature. The variant was identified in dbSNP (ID: rs36087757) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics and Myriad Women's Health). The variant was identified in control databases in 20 of 277230 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24032 chromosomes (freq: 0.000042), European in 11 of 126718 chromosomes (freq: 0.00009), East Asian in 8 of 18868 chromosomes (freq: 0.0004); it was not observed in the Other, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Val473 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).