Gene Validity Classification Summary

Gene/Disease Pair:

CDKN1B : multiple endocrine neoplasia type 4

HGNC:1785 | MONDO_0012552
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 4.5 4.5
Georgitsi M et al. 2007 Aug (PMID:17519308); Pellegata NS et al. 2006 Oct 17 (PMID:17030811); Tonelli F et al. 2014 Aug (PMID:24819502);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 6
4
4
Molatore S et al. 2010 Nov (PMID:20824794); Malanga D et al. 2012 Mar (PMID:22129891); Occhi G et al. 2013 Mar (PMID:23555276); Agarwal SK et al. 2009 May (PMID:19141585);
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  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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 1
0.5
1.5
Chu IM et al. 2008 Apr (PMID:18354415);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Molatore S et al. 2010 Nov (PMID:20824794); Occhi G et al. 2013 Mar (PMID:23555276);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Molatore S et al. 2010 Nov (PMID:20824794);
Models Non-human model organism 2 0 - 4 4 2 4 4
Pellegata NS et al. 2006 Oct 17 (PMID:17030811); Nakayama K et al. 1996 May 31 (PMID:8646779);
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 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
10/09/2018
EXPERT CURATION (DATE)
Definitive
12/21/2018
EVIDENCE SUMMARY
There is abundant evidence published associating the CDKN1B gene with multiple endocrine neoplasia type 4 (MEN4) since the gene-disease relationship was first proposed by Pellegata et al. (2006). Germline CDKN1B mutations are rare, but nine case level studies have been performed so far with MEN4 patients that have variants in the CDKN1B gene. CDKN1B is a negative regulator of cell cycle progression, and its loss is associated with disease progression and unfavorable outcome in many cancer types. CDKN1B show very low nuclear expression in parathyroid adenoma cells and endocrine pancreatic tumor from MEN4 patients. p27wt inhibits the growth of p27-negative GH3 cells in clonogenic assay while p27W76X does not. Mouse and Rat models have been established to show the development of multiple endocrine tumors with CDKN1B deficiency. All of these types of evidence are consistent with a definitive relationship between the CDKN1B gene and multiple endocrine neoplasia type 4 (MEN4).