ClinVar Genomic variation as it relates to human health

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.

In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 32658311 (2021), 32283892 (2020)), breast cancer (PMID: 29263802 (2016)), and healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1)). The frequency of this variant in the general population, 0.000087 (3/34592 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29263802, 32283892, 32658311, 22850631, 15235021)

This missense variant replaces valine with isoleucine at codon 787 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 29263802). This variant has been identified in 5/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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.

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 787 of the CDH1 protein (p.Val787Ile). This variant is present in population databases (rs766270336, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 29263802). ClinVar contains an entry for this variant (Variation ID: 186394). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: CDH1 c.2359G>A (p.Val787Ile) results in a conservative amino acid change in 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 2e-05 in 251458 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2359G>A has been reported in the literature in individuals affected with Breast Cancer or Colorectal Cancer without strong evidence of causality (e.g. Wong_2016, Wedem_2020, Akcay_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast 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: 29263802, 32283892, 32658311). ClinVar contains an entry for this variant (Variation ID: 186394). Based on the evidence outlined above, the variant was classified as uncertain significance.

The CDH1 p.Val787Ile variant was identified in 1 of 440 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Wong 2016 PMID: 29263802). The variant was also identified in dbSNP (ID: rs766270336 as With Uncertain significance allele) and ClinVar (2x as a variant of uncertain significance). The variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or Zhejiang University Database. The variant was identified in control databases in 5 of 246242 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 15302 chromosomes (freq: 0.00007), Latino in 3 of 33582 chromosomes (freq: 0.00009), European Non-Finnish in 1 of 111704 chromosomes (freq: 0.000009), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Val787 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not reliably predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.