Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NBN : Nijmegen breakage syndrome

HGNC:7652 | MONDO_0009623
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
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
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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 7
Varon R et al. 1998 May 1 (PMID:9590180); Nakanishi K et al. 2002 Dec (PMID:12447395);
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 2
Waltes R et al. 2009 May (PMID:19409520); Stewart GS et al. 1999 Dec 10 (PMID:10612394);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Nakanishi K et al. 2002 Dec (PMID:12447395); Plisiecka-Hałasa J et al. 2002 Nov (PMID:12485469);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 3 5 4
Williams BR et al. 2002 Apr 16 (PMID:11967151); Demuth I et al. 2004 Oct 15 (PMID:15333589); Dumon-Jones V et al. 2003 Nov 1 (PMID:14612522);
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
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
There has been sufficient amount of evidence published associating the NBN gene with Nijmegen breakage syndrome since the gene-disease relationship was first proposed by Varon et al. (1998). Multiple case level studies have been performed with NBS patients that have variants in the NBN gene. RAD50, another component of the MRE11-RAD50-NBN (MRN) complex, also causes Nijmegen breakage syndrome-like disorder. ATM and MRE11 are associated with an ataxia-telangiectasia(-like) disorder which shares a number of features in common with NBS. Immunoblotting demonstrates no nibrin protein expression in patient cells. Multiple NBN deficient mouse models have been established to show consistent phenotypes with NBS patients, including increased sensitivity to ionizing radiation, loss of the G2/M checkpoint, increased chromosome damage and susceptible to tumor development. All of these types of evidence are consistent with a definitive relationship between the NBN gene and Nijmegen breakage syndrome.