Gene Validity Curation

MEN1 - multiple endocrine neoplasia type 1

Gene: MEN1 (HGNC:7010)
Classification - 05/14/2020
Disease: multiple endocrine neoplasia type 1 (MONDO_0007540)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP Contributors:
  • UNC Biocuration Core
  • Hereditary Cancer GCEP
Evidence Summary: Multiple endocrine neoplasia type 1 (MEN1) is a complex syndrome defined by the neoplastic transformation of at least two endocrine organs, most frequently parathyroid glands, pancreatic islets, anterior pituitary and endocrine pancreas. There is abundant evidence published associating the MEN1 gene with multiple endocrine neoplasia type 1, since the gene-disease relationship was first proposed by Chandrasekharappa SC, et al., 1997 (PMID: 9103196). Multiple case level studies have been performed with MEN1 patients that have variants in the MEN1 gene. The variants include single amino acid changes or deletions that affect the stability of the protein and nonsense or frameshift LOF variants. A significant amount of case-level data is available; the maximum points for genetic evidence has been reached (12 points). Multiple mouse models of MEN1 have been established to show development of tumors consistent with MEN1 syndrome. In summary, MEN1 is definitively associated with the autosomal autosomal dominant Multiple Endocrine Neoplasia Type 1 syndrome. This has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
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 8 12.5 10
Chandrasekharappa SC et al. 1997 Apr 18 (PMID:9103196); Kim BY et al. 2017 Oct 2 (PMID:28969599);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 4
6
6
Chandrasekharappa SC et al. 1997 Apr 18 (PMID:9103196);
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) 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
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 4 4
Mohr H et al. 2017 Oct (PMID:28743793);
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) 4

 


 

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 4 16 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
05/14/2020
EXPERT CURATION (DATE)
Definitive
05/14/2020
EVIDENCE SUMMARY
Multiple endocrine neoplasia type 1 (MEN1) is a complex syndrome defined by the neoplastic transformation of at least two endocrine organs, most frequently parathyroid glands, pancreatic islets, anterior pituitary and endocrine pancreas. There is abundant evidence published associating the MEN1 gene with multiple endocrine neoplasia type 1, since the gene-disease relationship was first proposed by Chandrasekharappa SC, et al., 1997 (PMID: 9103196). Multiple case level studies have been performed with MEN1 patients that have variants in the MEN1 gene. The variants include single amino acid changes or deletions that affect the stability of the protein and nonsense or frameshift LOF variants. A significant amount of case-level data is available; the maximum points for genetic evidence has been reached (12 points). Multiple mouse models of MEN1 have been established to show development of tumors consistent with MEN1 syndrome. In summary, MEN1 is definitively associated with the autosomal autosomal dominant Multiple Endocrine Neoplasia Type 1 syndrome. This has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time.