chr16-68829757-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_004360.5(CDH1):c.2399G>A(p.Arg800His) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,613,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R800C) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
CDH1
NM_004360.5 missense
NM_004360.5 missense
Scores
8
10
1
Clinical Significance
Conservation
PhyloP100: 6.65
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP6
?
Variant 16-68829757-G-A is Benign according to our data. Variant chr16-68829757-G-A is described in ClinVar as [Benign]. Clinvar id is 142363.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH1 | NM_004360.5 | c.2399G>A | p.Arg800His | missense_variant | 15/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.2216G>A | p.Arg739His | missense_variant | 14/15 | ||
CDH1 | NM_001317185.2 | c.851G>A | p.Arg284His | missense_variant | 15/16 | ||
CDH1 | NM_001317186.2 | c.434G>A | p.Arg145His | missense_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.2399G>A | p.Arg800His | missense_variant | 15/16 | 1 | NM_004360.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000198 AC: 3AN: 151740Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251258Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135830
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461870Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727240
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ClinVar
Significance: Benign
Submissions summary: Uncertain:4Benign:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:2Benign:2
Benign, criteria provided, single submitter | clinical testing | European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto | Aug 01, 2022 | BS2; BP2_Strong (PMID: 30311375) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 06, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 04, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 17, 2023 | This missense variant replaces arginine with histidine at codon 800 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 intestinal-type gastric cancer (PMID: 26072394). This variant has been identified in 4/251258 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 15, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 02, 2021 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2017 | This variant is denoted CDH1 c.2399G>A at the cDNA level, p.Arg800His (R800H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in at least one individual with gastric cancer (van der Post 2015). CDH1 Arg800His was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. CDH1 Arg800His occurs at a position that is conserved across species and is located in the cytoplasmic domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CDH1 Arg800His is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
Benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 10, 2023 | The c.2399G>A (p.Arg800His) variant has an allele frequency of 0.00003 (0.003%, 1/30,614 alleles) in the South Asian gnomAD subpopulation (http://gnomad.broadinstitute.org). The variant has been seen in >10 individuals without DCG, SRC tumors, or LBC and whose families do not suggest HDGC (BS2; PMID: 26072394, SCV000186429.5, SCV000210876.13, SCV000254822.4). The variant has been identified in the homozygous state in an individual without personal and family history of DGC, LBC, or SRC tumors (BP2_Strong; SCV000186429.5). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
T;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D
REVEL
Uncertain
Sift
Pathogenic
D;.;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at