rs1064793437
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_004360.5(CDH1):c.298G>A(p.Val100Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V100A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.298G>A | p.Val100Ile | missense_variant | 3/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.298G>A | p.Val100Ile | missense_variant | 3/15 | ||
CDH1 | NM_001317185.2 | c.-1318G>A | 5_prime_UTR_variant | 3/16 | |||
CDH1 | NM_001317186.2 | c.-1522G>A | 5_prime_UTR_variant | 3/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.298G>A | p.Val100Ile | missense_variant | 3/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 13, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2023 | The p.V100I variant (also known as c.298G>A), located in coding exon 3 of the CDH1 gene, results from a G to A substitution at nucleotide position 298. The valine at codon 100 is replaced by isoleucine, an amino acid with highly similar properties. In one study, this alteration was not observed in 7051 unselected female breast cancer patients and was observed in 1/11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is well conserved in available vertebrate species; however, isoleucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 100 of the CDH1 protein (p.Val100Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 418791). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2018 | This variant is denoted CDH1 c.298G>A at the cDNA level, p.Val100Ile (V100I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. CDH1 Val100Ile was not observed in large population cohorts (Lek 2016). This variant is located in the precursor sequence domain (Brooks-Wilson 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDH1 Val100Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at