Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CDH1 : hereditary diffuse gastric adenocarcinoma

HGNC:1748 | MONDO_0007648
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hereditary Cancer
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10 8 10.5 10
Richards FM et al. 1999 Apr (PMID:10072428); Frebourg T et al. 2006 Feb (PMID:15831593); Guilford P et al. 1998 Mar 26 (PMID:9537325); Oliveira C et al. 2009 May 1 (PMID:19168852);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3
2
2
Suriano G et al. 2003 Mar 1 (PMID:12588804); Guilford P et al. 1998 Mar 26 (PMID:9537325);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.51 1
Frebourg T et al. 2006 Feb (PMID:15831593);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.51    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
1
Kemler R et al. 1993 Sep (PMID:8236461);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Shimoyama Y et al. 1991 Apr 15 (PMID:2009537);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 1 1
Suriano G et al. 2003 Nov 15 (PMID:14500541);
Models Non-human model organism 2 0 - 4 4 1 2 4
Perl AK et al. 1998 Mar 12 (PMID:9515965);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Perl AK et al. 1998 Mar 12 (PMID:9515965);
Rescue in cell culture model 1 0 - 2 1 1
Vleminckx K et al. 1991 Jul 12 (PMID:2070412);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
04/19/2019
EXPERT CURATION (DATE)
Definitive
04/19/2019
EVIDENCE SUMMARY
There is abundant published evidence associating the CDH1 gene with hereditary diffuse gastric cancer since the gene-disease relationship was first proposed by Guilford et al. (1998). Multiple case level studies have been performed with gastric cancer patients that have variants in the CDH1 gene. CDH1 is a calcium dependent cell-cell adhesion E-cadherin involved in the formation, maintenance and function of epithelial cells and it expresses in Gastric Carcinomas. Loss of E-cadherin expression coincides with the transition from well differentiated adenoma to invasive carcinoma in a transgenic mouse model of pancreatic b-cell carcinogenesis (Rip1Tag2). Carcinoma formation can be rescued when intercrossing Rip1Tag2 mice with transgenic mice that maintain E-cadherin expression in beta-tumour cells. The invasion can also be reversed when expressing E-cadherin in tumorigenic epitheiiai cells. The effect of E-cadherin germline missense mutations on cell morphology, motility and proliferation has been characterised in an E-cadherin negative epithelial cell line. All of these types of evidence are consistent with a definitive relationship between the CDH1 gene and hereditary diffuse gastric cancer.