chr16-68738340-G-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM2PP3_ModerateBP6_Very_Strong
The NM_004360.5(CDH1):c.92G>T(p.Gly31Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G31D) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Consequence
CDH1
NM_004360.5 missense
NM_004360.5 missense
Scores
4
11
4
Clinical Significance
Conservation
PhyloP100: 4.71
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 Likely_benign. Variant got -4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.91
BP6
?
Variant 16-68738340-G-T is Benign according to our data. Variant chr16-68738340-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 428635.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.92G>T | p.Gly31Val | missense_variant | 2/16 | ENST00000261769.10 | |
CDH1 | NM_001317184.2 | c.92G>T | p.Gly31Val | missense_variant | 2/15 | ||
CDH1 | NM_001317185.2 | c.-1524G>T | 5_prime_UTR_variant | 2/16 | |||
CDH1 | NM_001317186.2 | c.-1728G>T | 5_prime_UTR_variant | 2/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH1 | ENST00000261769.10 | c.92G>T | p.Gly31Val | missense_variant | 2/16 | 1 | NM_004360.5 | P1 | |
CDH1 | ENST00000422392.6 | c.92G>T | p.Gly31Val | missense_variant | 2/15 | 1 | |||
CDH1 | ENST00000566612.5 | c.92G>T | p.Gly31Val | missense_variant, NMD_transcript_variant | 2/15 | 1 | |||
CDH1 | ENST00000566510.5 | c.92G>T | p.Gly31Val | missense_variant, NMD_transcript_variant | 2/15 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely benign
Submissions summary: Uncertain:2Benign:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary diffuse gastric adenocarcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 30, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 428635). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 31 of the CDH1 protein (p.Gly31Val). - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 31, 2023 | The p.G31V variant (also known as c.92G>T), located in coding exon 2 of the CDH1 gene, results from a G to T substitution at nucleotide position 92. The glycine at codon 31 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen CDH1 Variant Curation Expert Panel | Aug 02, 2023 | The c.92G>T (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Gly by Val at amino acid 31 (p.Gly31Val) in exon 2. This variant was observed in more than ten individuals with no DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; Invitae, Ambry). This variant is absent from gnomAD 2.1.1 (PM2_Spporting). In summary, this variant meets the criteria to be classified as likely benign for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2. (CDH1 VCEP specifications version 3.1; 05/06/2022) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;.;.;.;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;.;.;.;D
REVEL
Uncertain
Sift
Benign
T;.;.;.;T
Sift4G
Uncertain
D;D;D;D;D
Polyphen
P;.;.;.;.
Vest4
MutPred
Loss of disorder (P = 0.0376);Loss of disorder (P = 0.0376);Loss of disorder (P = 0.0376);Loss of disorder (P = 0.0376);Loss of disorder (P = 0.0376);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at