rs1555515597

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_004360.5(CDH1):​c.833G>A​(p.Gly278Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. G278R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CDH1
NM_004360.5 missense, splice_region

Scores

8
9
2
Splicing: ADA: 0.8723
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.08
Variant links:
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 Pathogenic. Variant got 10 ACMG points.

PM1
In a domain Cadherin 2 (size 112) in uniprot entity CADH1_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_004360.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-68810341-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH1NM_004360.5 linkc.833G>A p.Gly278Glu missense_variant, splice_region_variant Exon 7 of 16 ENST00000261769.10 NP_004351.1 P12830-1A0A0U2ZQU7B3GN61

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkc.833G>A p.Gly278Glu missense_variant, splice_region_variant Exon 7 of 16 1 NM_004360.5 ENSP00000261769.4 P12830-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1
Apr 16, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces glycine with glutamic acid at codon 278 of the CDH1 protein (p.Gly278Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDH1-related disease. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1
Feb 06, 2019
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.G278E variant (also known as c.833G>A) is located in coding exon 7 of the CDH1 gene. The glycine at codon 278 is replaced by glutamic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 7. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
29
DANN
Benign
0.94
DEOGEN2
Uncertain
0.62
D;T;T;.;.
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.86
D;D;D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D
MetaSVM
Uncertain
0.48
D
MutationAssessor
Pathogenic
3.6
H;.;.;.;H
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-7.3
D;.;.;.;D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0010
D;.;.;.;D
Sift4G
Uncertain
0.0030
D;D;D;D;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.92
MutPred
0.90
Gain of disorder (P = 0.0611);Gain of disorder (P = 0.0611);Gain of disorder (P = 0.0611);Gain of disorder (P = 0.0611);Gain of disorder (P = 0.0611);
MVP
0.93
MPC
1.0
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.91
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.87
dbscSNV1_RF
Benign
0.61
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555515597; hg19: chr16-68845587; API