Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

MET : papillary renal cell carcinoma

HGNC:7029 | MONDO_0017884
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 3
5
5
Lubensky IA et al. 1999 Aug (PMID:10433944);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 7
10.5
7
Schmidt L et al. 1997 May (PMID:9140397); Lubensky IA et al. 1999 Aug (PMID:10433944);
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 1.5 1.5  
Candidate gene sequencing 7.83 3
Schmidt L et al. 1997 May (PMID:9140397); Lubensky IA et al. 1999 Aug (PMID:10433944);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 7.83    
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
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Prat M et al. 1991 Sep 30 (PMID:1917129);
Functional Alteration Patient cells 1 0 - 2 2
1.5
Non-patient cells 0.5 0 - 1 2 1.5
Bellon SF et al. 2008 Feb 1 (PMID:18055465); Jeffers M et al. 1997 Oct 14 (PMID:9326629);
Models Non-human model organism 2 0 - 4 4 2 4 4
Graveel C et al. 2004 Dec 7 (PMID:15557554); Boccaccio C et al. 2005 Mar 17 (PMID:15772665);
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) 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
10/11/2018
EXPERT CURATION (DATE)
Definitive
10/11/2018
EVIDENCE SUMMARY
There is abundant published evidence associating the MET gene with papillary renal cell carcinoma since the gene-disease relationship was first proposed by Schmidt et al. (1997). Multiple case level studies have been performed with RCCP patients that have variants in the MET gene. Since gain of function is the disease mechanism, all pathogenic variants reported so far are missense variants. MET expresses in hepatocytes, epithelial cells and kidney. MET mutants exhibit increased levels of tyrosine phosphorylation and enhanced kinase activity in cell assays. Mutant MET molecules form foci in vitro and are tumorigenic in nude mice. Multiple MET knock-in in vivo mouse models of the kinase domain mutations have been established to show consistent phenotypes of tumorigenesis with RCCP patients. All of these types of evidence are consistent with a definitive relationship between the MET gene and papillary renal cell carcinoma.