rs1555516545

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5_SupportingPVS1PM2_SupportingPS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1612delG p.(Asp538Thrfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID:29131691). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA645509536/MONDO:0007648/007

Frequency

Genomes: not found (cov: 32)

Consequence

CDH1
NM_004360.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: -4.08
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 11 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH1NM_004360.5 linkuse as main transcriptc.1612delG p.Asp538fs frameshift_variant 11/16 ENST00000261769.10 NP_004351.1 P12830-1A0A0U2ZQU7B3GN61
CDH1NM_001317184.2 linkuse as main transcriptc.1429delG p.Asp477fs frameshift_variant 10/15 NP_001304113.1 P12830-2B3GN61
CDH1NM_001317185.2 linkuse as main transcriptc.64delG p.Asp22fs frameshift_variant 11/16 NP_001304114.1 P12830B3GN61Q9UII7
CDH1NM_001317186.2 linkuse as main transcriptc.-254-2675delG intron_variant NP_001304115.1 P12830B3GN61

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.1612delG p.Asp538fs frameshift_variant 11/161 NM_004360.5 ENSP00000261769.4 P12830-1

Frequencies

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

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingEuropean Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of PortoAug 01, 2022PVS1; PS4_Supporting; PM2 (PMID: 30311375) -
Pathogenic, criteria provided, single submitterresearchImmunopatologia e Biomarcatori Oncologici/Bio-proteomics facility, Centro di Riferimento OncologicoJan 02, 2017age<50 years, diffuse type, male, clinical aggressive form -
CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1
Pathogenic, reviewed by expert panelcurationClinGen CDH1 Variant Curation Expert PanelAug 25, 2023The c.1612delG p.(Asp538Thrfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 29131691). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1555516545; hg19: chr16-68853227; API