Gene Validity Curation

CDK4 - melanoma, cutaneous malignant, susceptibility to, 3

Gene: CDK4 (HGNC:1773)
Classification - 01/13/2020
Disease: melanoma, cutaneous malignant, susceptibility to, 3 (MONDO_0012183)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: CDK4 was the second high risk melanoma susceptibility gene identified . CDK4 is an oncogene located within the 12q14 chromosomal region and encodes a protein that controls cell cycle progression through the G1 phase. To date mutations in this gene have been described in 17 melanoma-prone families and in all of them the mutation affects the same amino acid (Arginine 24): p.Arg24Cys and p.Arg24His (Potrony M, et al. 2015. PMID: 26488006). These R24C and R24H mutations lead to CDK4 behaving as a dominant oncoprotein through loss of binding to p16, its negative regulator. Thus, when CDK4 is mutated, p16INK4A cannot inhibit the CDK4 kinase activity resulting in the progression of the cell cycle. In an analysis of 17 families, median age at first melanoma diagnosis was 39 years, and the lifetime mutation penetrance based on the available data was estimated at 74%(Read J, et al. 2016.PMID: 26337759). Phenotypically, individuals with CDK4 mutations cannot be distinguished from those with CDKN2A mutations . Both mutations are characterized by numerous atypical nevi and multiple primary melanomas.(Lee KC, et al. 2015. PMID:30190834).
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
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 10
9
7
Zuo L et al. 1996 Jan (PMID:8528263); Puntervoll HE et al. 2013 Apr (PMID:23384855); Soufir N et al. 1998 Feb (PMID:9425228); Molven A et al. 2005 Sep (PMID:15880589);
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 13.26 4
Zuo L et al. 1996 Jan (PMID:8528263); Soufir N et al. 1998 Feb (PMID:9425228); Molven A et al. 2005 Sep (PMID:15880589);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 13.26    
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) 8.5
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 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
1.5
Non-patient cells 0.5 0 - 1 2 1.5
Wölfel T et al. 1995 Sep 1 (PMID:7652577); Kollmann K et al. 2019 Feb 15 (PMID:30858922);
Models Non-human model organism 2 0 - 4 4 1 2 4
Rane SG et al. 2002 Jan (PMID:11756559);
Cell culture model 1 0 - 2 1 2
Rane SG et al. 2002 Jan (PMID:11756559);
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 8.5 6 14.5 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
12/19/2019
EXPERT CURATION (DATE)
Definitive
01/13/2020
EVIDENCE SUMMARY
CDK4 was the second high risk melanoma susceptibility gene identified . CDK4 is an oncogene located within the 12q14 chromosomal region and encodes a protein that controls cell cycle progression through the G1 phase. To date mutations in this gene have been described in 17 melanoma-prone families and in all of them the mutation affects the same amino acid (Arginine 24): p.Arg24Cys and p.Arg24His (Potrony M, et al. 2015. PMID: 26488006). These R24C and R24H mutations lead to CDK4 behaving as a dominant oncoprotein through loss of binding to p16, its negative regulator. Thus, when CDK4 is mutated, p16INK4A cannot inhibit the CDK4 kinase activity resulting in the progression of the cell cycle. In an analysis of 17 families, median age at first melanoma diagnosis was 39 years, and the lifetime mutation penetrance based on the available data was estimated at 74%(Read J, et al. 2016.PMID: 26337759). Phenotypically, individuals with CDK4 mutations cannot be distinguished from those with CDKN2A mutations . Both mutations are characterized by numerous atypical nevi and multiple primary melanomas.(Lee KC, et al. 2015. PMID:30190834).