GeneBe

rs587782476

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3

The NM_004360.5(CDH1):​c.38_46delTGCTGCTGC​(p.Leu13_Leu15del) variant causes a disruptive inframe deletion, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L13L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

CDH1
NM_004360.5 disruptive_inframe_deletion, splice_region

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.93

Publications

2 publications found
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]
CDH1 Gene-Disease associations (from GenCC):
  • blepharocheilodontic syndrome 1
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
  • CDH1-related diffuse gastric and lobular breast cancer syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
  • hereditary breast carcinoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
  • hereditary diffuse gastric adenocarcinoma
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
  • cleft soft palate
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • orofacial cleft 3
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • blepharocheilodontic syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial ovarian cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP3
Nonframeshift variant in repetitive region in NM_004360.5

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH1NM_004360.5 linkc.38_46delTGCTGCTGC p.Leu13_Leu15del disruptive_inframe_deletion, splice_region_variant Exon 1 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.38_46delTGCTGCTGC p.Leu13_Leu15del disruptive_inframe_deletion, splice_region_variant Exon 1 of 16 1 NM_004360.5 ENSP00000261769.4 P12830-1
CDH1ENST00000422392.6 linkc.38_46delTGCTGCTGC p.Leu13_Leu15del disruptive_inframe_deletion, splice_region_variant Exon 1 of 15 1 ENSP00000414946.2 P12830-2
CDH1ENST00000566612.5 linkn.38_46delTGCTGCTGC splice_region_variant, non_coding_transcript_exon_variant Exon 1 of 15 1 ENSP00000454782.1 H3BNC6
CDH1ENST00000566510.5 linkn.38_46delTGCTGCTGC splice_region_variant, non_coding_transcript_exon_variant Exon 1 of 15 5 ENSP00000458139.1 H3BVI7

Frequencies

GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
33

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
May 10, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). 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. Studies have shown that this variant alters CDH1 gene expression (PMID: 30068367). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 30068367). This variant, c.38_46del, results in the deletion of 3 amino acid(s) of the CDH1 protein (p.Leu13_Leu15del), but otherwise preserves the integrity of the reading frame. -

Hereditary cancer-predisposing syndrome Uncertain:1
Nov 13, 2018
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.9
Mutation Taster
=13/187
disease causing

Splicing

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

Publications

Other links and lift over

dbSNP: rs587782476; hg19: chr16-68771347; API