GeneBe

rs1555516200

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP1_ModeratePM5_SupportingPM2_SupportingPS4PP3_ModeratePVS1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1565+2dupT variant is a intronic variant in the donor region of intron 10 (PVS1_Strong, PM5_Supporting). This variant affects the same splice site as a well-characterized splice variant with similar or worse in silico/RNA predictions (PP3_Moderate). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). It has been reported in at least six families meeting HDGC clinical criteria (PS4; PMID:18391748, 23709761, 25315765, 26072394, SCV000665426.2), and was also found to co-segregate with disease in multiple affected family members with 5 meioses observed (PP1_Moderate; PMID:25315765, 22020549, SCV000665426.2). 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_Strong, PS4, PM2_Supporting, PM5_Supporting, PP1_Moderate, PP3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16614980/MONDO:0007648/007

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CDH1
ENST00000261769.10 splice_donor, intron

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:12

Conservation

PhyloP100: 7.46

Publications

0 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, Labcorp Genetics (formerly Invitae), G2P, Illumina
  • CDH1-related diffuse gastric and lobular breast cancer syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
  • hereditary breast carcinoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
  • hereditary diffuse gastric adenocarcinoma
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
  • 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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 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.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261769.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
CDH1
NM_004360.5
MANE Select
c.1565+2dupT
splice_region intron
N/ANP_004351.1A0A0U2ZQU7
CDH1
NM_001317184.2
c.1382+2dupT
splice_region intron
N/ANP_001304113.1P12830-2
CDH1
NM_001317185.2
c.17+2dupT
splice_region intron
N/ANP_001304114.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
CDH1
ENST00000261769.10
TSL:1 MANE Select
c.1565+1_1565+2insT
splice_donor intron
N/AENSP00000261769.4P12830-1
CDH1
ENST00000422392.6
TSL:1
c.1382+1_1382+2insT
splice_donor intron
N/AENSP00000414946.2P12830-2
CDH1
ENST00000562836.5
TSL:1
n.1636+1_1636+2insT
splice_donor intron
N/A

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461860
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727226
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112000
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
5
-
-
Hereditary diffuse gastric adenocarcinoma (5)
3
-
-
not provided (3)
2
-
-
Hereditary cancer-predisposing syndrome (2)
1
-
-
CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
1
-
-
Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
7.5
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.63
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.63
Position offset: 5
DS_DL_spliceai
0.47
Position offset: -1

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

Publications

Other links and lift over

dbSNP: rs1555516200; hg19: chr16-68849663; API