Gene Validity Classification Summary

Gene/Disease Pair:

CDH1 : Hereditary breast cancer

HGNC:1748 | OrphaNet: 26106 | OMIM:114480
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
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 10.0 10
Xie ZM et al. 2011 Jul 15 (PMID:21271559); Hansford S et al. 2015 Apr (PMID:26182300); Benusiglio PR et al. 2013 Jul (PMID:23709761); Petridis C et al. 2014 Feb 18 (PMID:24366306); Masciari S et al. 2007 Nov (PMID:17660459);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
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 Evidence of segregation in one or more families LOD Score Examples 3 5 0-7 7 1.5 1.5
Xie ZM et al. 2011 Jul 15 (PMID:21271559);
2 4
1.5 3
1 1.5
   
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6 12 2.0 2
Kurian AW et al. 2014 Jul 1 (PMID:24733792);
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 2.0 2
Kanai Y et al. 1994 Oct (PMID:7961105); Frixen UH et al. 1991 Apr (PMID:2007622); Jaspersen SL et al. 1999 Mar 11 (PMID:10074450);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1.0 1
van Horssen R et al. 2012 Nov (PMID:23053649);
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 3.0 3
Frixen UH et al. 1991 Apr (PMID:2007622); Derksen PW et al. 2006 Nov (PMID:17097565); Figueiredo J et al. 2013 Mar (PMID:22850631);
Cell culture model system 1 0 - 2
Rescue in animal model 2 0 - 4
Rescue in engineered equivalent 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)*
CALCULATED CLASSIFICATION (DATE)
DEFINITIVE
01/25/2017
EXPERT CURATION (DATE)
DEFINITIVE
01/25/2017