Gene Validity Classification Summary

Gene/Disease Pair:

CDKN2A : melanoma-pancreatic cancer syndrome

HGNC:1787 | MONDO_0011713
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Hereditary Cancer EP
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 3 5.5 5.5
Gruis NA et al. 1995 Jul (PMID:7670475); Harinck F et al. 2012 Jun (PMID:22636603); Binni F et al. 2010 Jun (PMID:20132244);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4
5
5
Whelan AJ et al. 1995 Oct 12 (PMID:7666917); Borg A et al. 1996 Jun 1 (PMID:8653684); Binni F et al. 2010 Jun (PMID:20132244); Pollock PM et al. 1998 (PMID:9603434);
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 9.34 4
Gruis NA et al. 1995 Jul (PMID:7670475); Whelan AJ et al. 1995 Oct 12 (PMID:7666917); Borg A et al. 1996 Jun 1 (PMID:8653684); Harinck F et al. 2012 Jun (PMID:22636603);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 9.34    
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 1 0.5
Wölfel T et al. 1995 Sep 1 (PMID:7652577);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
2
Non-patient cells 0.5 0 - 1 2 2
McKenzie HA et al. 2010 Jun (PMID:20340136);
Models Non-human model organism 2 0 - 4 4 2 4 4
Krimpenfort P et al. 2007 Aug 23 (PMID:17713536); Krimpenfort P et al. 2001 Sep 6 (PMID:11544530);
Cell culture model 1 0 - 2 1 1
Krimpenfort P et al. 2007 Aug 23 (PMID:17713536);
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
10/09/2018
EXPERT CURATION (DATE)
Definitive
12/21/2018
EVIDENCE SUMMARY
There is abundant evidence published associating the CDKN2A gene with melanoma-pancreatic cancer syndrome since the gene-disease relationship was first proposed by Hussussian et al. (1994). Multiple case level studies have been performed with melanoma patients that have variants in the CDKN2A gene. Over 200 families has been reported worldwide and many variants are founder variants. CDK4 that is inhibited by p16 is also associate with Melanoma, cutaneous malignant. Assessment of CDK4 binding and p16 subcellular localization can accurately and rapidly determine the functional significance of melanoma associated p16INK4a mutations. Multiple in vivo knock-out mouse models with CDKN2A deficiency have been established to show tumorigenesis of melanoma and other types of tumors. All of these types of evidence are consistent with a definitive relationship between the CDKN2A gene and melanoma-pancreatic cancer syndrome.