Gene Validity Curation

KIT - gastrointestinal stromal tumor

Gene: KIT (HGNC:6342)
Classification - 01/14/2020
Disease: gastrointestinal stromal tumor (MONDO_0011719)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: KIT gene (21 exons) encodes the 145 kDa receptor tyrosine kinase c-KIT with an extracellular domain, a juxtamembrane domain, tyrosine kinase domain I and tyrosine kinase domain II. c-KIT is maintained in an inactive form through auto-inhibition of the kinase domain. The binding of Stem cell factor (SCF), a KIT ligand, promotes dimerization of the enzyme, ATP binding to the tyrosine kinase domain and auto phosphorylation of the tyrosine residue in the juxtamembrane domain . This process activates downstream pathways. Most of the KIT germline variants are gain of function (GoF), which cause autonomous kinase activation in the absence of ligand SCF binding. Genetics evidences recorded here are from unrelated families (Germany, Japan, France, Belgium and Italy) with variants cosegregating with GIST. Majority of the variants are missense or in frame deletions. Functional studies showed autonomous kinase activation both in cell cultures and nude mice. Imatinib can inhibit the autonomous phosphorylation and achieved long term partial response or stable disease in treated patients. LOD scores from two large families, that had enough affected and unaffected individuals tested and proved cosegregation in at least 3 generations are counted in this curation. Mouse knock in models of corresponding human mutations KIT Asp820Tyr, Val559del and Lys641Glu result in similar phenotypes consistent with KIT GoF mutations. The definitive role of KIT gene in GISTs had been replicated in many genetic and functional studies over time.
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 1
1
1
Graham J et al. 2007 Sep (PMID:17824795);
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 9
11.5
7
Thalheimer A et al. 2008 Oct (PMID:18724244); Hartmann K et al. 2005 Sep (PMID:16143141); Nishida T et al. 1998 Aug (PMID:9697690); Woźniak A et al. 2008 May 1 (PMID:18183595); Isozaki K et al. 2000 Nov (PMID:11073817); Beghini A et al. 2001 Aug 1 (PMID:11505412); Maeyama H et al. 2001 Jan (PMID:11208730); Hirota S et al. 2002 May (PMID:11984533); Robson ME et al. 2004 Feb 15 (PMID:14977822);
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 5.72 2
Nishida T et al. 1998 Aug (PMID:9697690); Robson ME et al. 2004 Feb 15 (PMID:14977822);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 5.72    
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) 9.5
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
Hirota S et al. 2002 May (PMID:11984533);
Functional Alteration Patient cells 1 0 - 2 2
2
Non-patient cells 0.5 0 - 1 4 2
Nishida T et al. 1998 Aug (PMID:9697690); Isozaki K et al. 2000 Nov (PMID:11073817);
Models Non-human model organism 2 0 - 4 4 5 10 4
Nishida T et al. 1998 Aug (PMID:9697690); Isozaki K et al. 2000 Nov (PMID:11073817); Nakai N et al. 2008 Feb (PMID:18098338); Rubin BP et al. 2005 Aug 1 (PMID:16061643); Sommer G et al. 2003 May 27 (PMID:12754375);
Cell culture model 1 0 - 2 1 1
Hartmann K et al. 2005 Sep (PMID:16143141);
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 9.5 6 15.5 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)
Definitive
01/14/2020
EXPERT CURATION (DATE)
Definitive
01/14/2020
EVIDENCE SUMMARY
KIT gene (21 exons) encodes the 145 kDa receptor tyrosine kinase c-KIT with an extracellular domain, a juxtamembrane domain, tyrosine kinase domain I and tyrosine kinase domain II. c-KIT is maintained in an inactive form through auto-inhibition of the kinase domain. The binding of Stem cell factor (SCF), a KIT ligand, promotes dimerization of the enzyme, ATP binding to the tyrosine kinase domain and auto phosphorylation of the tyrosine residue in the juxtamembrane domain . This process activates downstream pathways. Most of the KIT germline variants are gain of function (GoF), which cause autonomous kinase activation in the absence of ligand SCF binding. Genetics evidences recorded here are from unrelated families (Germany, Japan, France, Belgium and Italy) with variants cosegregating with GIST. Majority of the variants are missense or in frame deletions. Functional studies showed autonomous kinase activation both in cell cultures and nude mice. Imatinib can inhibit the autonomous phosphorylation and achieved long term partial response or stable disease in treated patients. LOD scores from two large families, that had enough affected and unaffected individuals tested and proved cosegregation in at least 3 generations are counted in this curation. Mouse knock in models of corresponding human mutations KIT Asp820Tyr, Val559del and Lys641Glu result in similar phenotypes consistent with KIT GoF mutations. The definitive role of KIT gene in GISTs had been replicated in many genetic and functional studies over time.