chr16-68829727-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004360.5(CDH1):​c.2369C>A​(p.Thr790Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 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. T790I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CDH1
NM_004360.5 missense

Scores

6
13

Clinical Significance

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

Conservation

PhyloP100: 1.52
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDH1NM_004360.5 linkuse as main transcriptc.2369C>A p.Thr790Asn missense_variant 15/16 ENST00000261769.10
CDH1NM_001317184.2 linkuse as main transcriptc.2186C>A p.Thr729Asn missense_variant 14/15
CDH1NM_001317185.2 linkuse as main transcriptc.821C>A p.Thr274Asn missense_variant 15/16
CDH1NM_001317186.2 linkuse as main transcriptc.404C>A p.Thr135Asn missense_variant 14/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.2369C>A p.Thr790Asn missense_variant 15/161 NM_004360.5 P1P12830-1

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 cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 04, 2018The p.T790N variant (also known as c.2369C>A), located in coding exon 15 of the CDH1 gene, results from a C to A substitution at nucleotide position 2369. The threonine at codon 790 is replaced by asparagine, an amino acid with similar properties. This amino acid position is not well conserved in available 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. -
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJul 26, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.075
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
18
DANN
Uncertain
0.98
DEOGEN2
Benign
0.30
T;T;.
Eigen
Benign
-0.018
Eigen_PC
Benign
-0.020
FATHMM_MKL
Benign
0.58
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Uncertain
0.43
T;T;T
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Benign
0.38
N;.;.
MutationTaster
Benign
0.94
D;D
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-2.6
D;.;N
REVEL
Benign
0.27
Sift
Benign
0.083
T;.;D
Sift4G
Benign
0.43
T;T;T
Polyphen
0.99
D;.;.
Vest4
0.37
MutPred
0.31
Loss of glycosylation at T790 (P = 0.028);.;.;
MVP
0.88
MPC
0.89
ClinPred
0.90
D
GERP RS
5.9
Varity_R
0.37
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs587780120; hg19: chr16-68863630; API