Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SUFU : medulloblastoma

HGNC:16466 | MONDO_0007959
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 1
2.5
2.5
Pastorino L et al. 2009 Jul (PMID:19533801);
Proband with predicted or proven null variant 1.5 0-2 10 6 8.5 8.5
Taylor MD et al. 2002 Jul (PMID:12068298); Brugières L et al. 2010 Feb (PMID:19833601); Smith MJ et al. 2014 Dec 20 (PMID:25403219);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0.5
0.5
Aavikko M et al. 2012 Sep 7 (PMID:22958902);
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 6.32 3
Brugières L et al. 2010 Feb (PMID:19833601); Aavikko M et al. 2012 Sep 7 (PMID:22958902);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.32    
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 2
1
1
Hahn H et al. 1996 Jun 14 (PMID:8681379); Fan Z et al. 2008 May (PMID:18285427);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 2 1
Taylor MD et al. 2002 Jul (PMID:12068298); Aavikko M et al. 2012 Sep 7 (PMID:22958902);
Models Non-human model organism 2 0 - 4 4 3 4.5 4
Svärd J et al. 2006 Feb (PMID:16459298); Lee Y et al. 2007 Sep 27 (PMID:17452975); Heby-Henricson K et al. 2012 Sep (PMID:21882258);
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 SUFU gene with medulloblastoma since the gene-disease relationship was first proposed by Taylor et al. (2002). Multiple case level studies have been performed with medulloblastoma patients that have variants in the SUFU gene. PTCH1 and PTCH2 are also related to dominantly inherited NBCCS and medulloblastoma. The effect of medulloblastoma-derived mutant of SUFU on Hedgehog signaling activity had been shown in cell assays. Multiple SUFU deficient mouse models have been established to show consistent phenotypes with medulloblastoma patients. Sufu+/- mice develop a Gorlin-like skin phenotype. Patients with SUFU mutations can exhibit medulloblastoma and features of Gorlin syndrome. In conjunction with p53 loss, Sufu+/- mice developed tumors including medulloblastoma and rhabdomyosarcoma. All of these types of evidence are consistent with a definitive relationship between the SUFU gene and medulloblastoma.