Gene Validity Curation

ALK - neuroblastoma, susceptibility to, 3

Gene: ALK (HGNC:427)
Classification - 11/21/2019
Disease: neuroblastoma, susceptibility to, 3 (MONDO_0013083)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer GCEP
Evidence Summary: There is sufficient evidence published suggesting that the gain of function mutations in the ALK gene is susceptible to neuroblastoma since the gene-disease relationship was firstly proposed by Mosse et al. (2008). Multiple studies of case level have been performed with families segregated with neuroblastoma, with incomplete penetrance. These families were detected with the germline mutations in the ALK gene, especially enriched in the tyrosine kinase domain. The pattern of disease in the ALK p.F1174L transgenic mice largely recapitulates the clinical spectrum of human neuroblastoma. In vitro studies suggested mutant ALK protein showed increased kinase activity and resulting in the cell proliferation. All of these evidences suggest a definitive relationship that mutant ALK gene is susceptible to neuroblastoma.
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 4
6
6
Mossé YP et al. 2008 Oct 16 (PMID:18724359); de Pontual L et al. 2011 Mar (PMID:21972109);
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 6
5
5
Mossé YP et al. 2008 Oct 16 (PMID:18724359); George RE et al. 2008 Oct 16 (PMID:18923525); Bourdeaut F et al. 2012 Mar (PMID:22071890);
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 1  
Candidate gene sequencing 4.23 1
Mossé YP et al. 2008 Oct 16 (PMID:18724359);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 4.23    
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
1.5
Non-patient cells 0.5 0 - 1 3 1.5
George RE et al. 2008 Oct 16 (PMID:18923525); Chen Y et al. 2008 Oct 16 (PMID:18923524); Bourdeaut F et al. 2012 Mar (PMID:22071890);
Models Non-human model organism 2 0 - 4 4 2 4 4
Chen Y et al. 2008 Oct 16 (PMID:18923524); Heukamp LC et al. 2012 Jul 4 (PMID:22764207);
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 1 1
Chen Y et al. 2008 Oct 16 (PMID:18923524);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5.5

 


 

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 5.5 17.5 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
10/02/2019
EXPERT CURATION (DATE)
Definitive
11/21/2019
EVIDENCE SUMMARY
There is sufficient evidence published suggesting that the gain of function mutations in the ALK gene is susceptible to neuroblastoma since the gene-disease relationship was firstly proposed by Mosse et al. (2008). Multiple studies of case level have been performed with families segregated with neuroblastoma, with incomplete penetrance. These families were detected with the germline mutations in the ALK gene, especially enriched in the tyrosine kinase domain. The pattern of disease in the ALK p.F1174L transgenic mice largely recapitulates the clinical spectrum of human neuroblastoma. In vitro studies suggested mutant ALK protein showed increased kinase activity and resulting in the cell proliferation. All of these evidences suggest a definitive relationship that mutant ALK gene is susceptible to neuroblastoma.