chr16-68833300-C-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4BP6_Very_StrongBS2
The NM_004360.5(CDH1):c.2450C>T(p.Ala817Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A817P) has been classified as Uncertain significance.
Frequency
Consequence
NM_004360.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2450C>T | p.Ala817Val | missense_variant | 16/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2267C>T | p.Ala756Val | missense_variant | 15/15 | ||
CDH1 | NM_001317185.2 | c.902C>T | p.Ala301Val | missense_variant | 16/16 | ||
CDH1 | NM_001317186.2 | c.485C>T | p.Ala162Val | missense_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2450C>T | p.Ala817Val | missense_variant | 16/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251458Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135908
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461674Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727166
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 06, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including colorectal cancer and glioma in published literature (Raskin et al., 2017; Frster et al., 2021); Published functional studies demonstrate a damaging effect: reduced cell aggregation, enhanced cell migration, and reduced B-catenin binding (Frster et al., 2021); This variant is associated with the following publications: (PMID: 23856246, 24163242, 26486520, 29212164, 33929593, 35598687, 15235021, 22850631) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 11, 2023 | The frequency of this variant in the general population, 0.000035 (4/113750 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 29212164 (2017)) and in a family with glioma (PMID: 33929593 (2021)). In addition, this variant has been reported in healthy control individuals (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). A functional study showed increased cell migration, impaired beta-catenin binding, and impaired beta-catenin cellular localization in a knock-in cellular model expressing this variant (PMID: 33929593 (2021)). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 21, 2020 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 21, 2023 | This missense variant replaces alanine with valine at codon 817 of the CDH1 protein. A functional study demonstrated the variant impacts cell migration and aggregation, membrane expression of E-cadherin, and interaction with B-catenin (PMID: 33929593). This variant has been reported in an individual affected with colorectal cancer with no history of gastric cancer (PMID: 29212164) and in an individual affected with lobular breast cancer who also carried a pathogenic variant in the TP53 gene (Riedlinger 2020, doi.org/10.21203/rs.3.rs-109612/v1). This variant has been identified in 6/251458 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. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 31, 2020 | - - |
CDH1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 12, 2024 | The CDH1 c.2450C>T variant is predicted to result in the amino acid substitution p.Ala817Val. This variant was reported in an individual with colorectal cancer and a father and his two offspring with glioma (Table S1, Raskin et al. 2017. PubMed ID: 29212164; Tables S2, S12, and S13, Sup. Fig. 1, Förster et al. 2021. PubMed ID: 33929593). In vitro experimental studies were inconclusive (Sup. Figs. 3-5, Förster et al. 2021. PubMed ID: 33929593). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141802/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 05, 2023 | - - |
Hereditary diffuse gastric adenocarcinoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Sep 25, 2023 | The c.2450C>T (p.Ala817Val) variant results in a missense change in the last exon of CDH1. This variant is present at a frequency 3.3x10-5 (5 of 152,172 alleles) in the gnomAD population database v3.1.2. This variant has been observed in 104 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; internal laboratory contributors). In vitro studies of the A817V variant suggest reduced binding of B-catenin and reduced cell aggregation in a HEK293T cell model (PMID: 33929593). However, evaluation of the use of functional data by the VCEP indicates that functional data currently available for missense variants cannot yet predict the pathogenicity of CDH1 variants, and it is therefore not considered in the classification for any CDH1 missense variant (Lee et al, 2018; PMID: 30311375). As such, published information from in vitro or in vivo assays assessing impact on function for this missense variant has not been considered for variant curation. In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at