Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

PTCH2 : nevoid basal cell carcinoma syndrome

HGNC:9586 | MONDO_0007187
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 1 1.5 1.5
Fujii K et al. 2013 Dec (PMID:23479190);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
1
1
Fan Z et al. 2008 May (PMID:18285427);
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 0.5 0.5  
Candidate gene sequencing 2.41 1
Fan Z et al. 2008 May (PMID:18285427);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 2.41    
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) 3
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 2
1
1
Hahn H et al. 1996 Jun 14 (PMID:8681379); Pastorino L et al. 2009 Jul (PMID:19533801);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1 1
Nieuwenhuis E et al. 2006 Sep (PMID:16914743);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2

 


 

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 3 2 5 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)
Limited
10/12/2018
EXPERT CURATION (DATE)
Limited
10/12/2018
EVIDENCE SUMMARY
There is one large family with a specific missense mutation (that is otherwise very rare in gnomAD) with a LOD score 2.41 and for which there is extensive functional studies with a Gorlin-like phenotype. The other report is a frameshift variant in a Japanese individual. The Ptch2 mouse knockout model showed related but milder phenotype with no tumors. The evidence that variants in PTCH2 cause a Gorlin-like phenotype (odontogenic cysts, etc) with milder phenotype and lower penetrance than the PTCH1-associated genotype is limited.