| Gene/Disease Pair: | NBN : Nijmegen breakage syndrome |
| HGNC:7652 | MONDO_0009623 | |
| Mode of Inheritance: | Autosomal recessive inheritance (HP:0000007) |
| Expert Panel: | Hereditary Cancer EP |
| SOP: | Gene Clinical Validity Standard Operating Procedures (SOP), Version 6 |
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Genetic Evidence
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Case-Level Data
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Evidence Type | Case Information Type | Guidelines | Points | PMIDs/Notes | |||||
| Default | Range | Max | Count | Total | Counted | ||||||
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Variant Evidence
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Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 |
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| 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 |
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| Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 | 7 |
15
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12 |
Varon R et al. 1998 May 1 (PMID:9590180); Nakanishi K et al. 2002 Dec (PMID:12447395);
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| 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 | |||||||||||
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Case-Control Data
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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 |
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| Aggregate Variant Analysis | 0-6 |
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| Total Genetic Evidence Points (Maximum 12) | 12 |
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Experimental Evidence
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Evidence Category | Evidence Type | Guidelines | Points | PMIDs/Notes | ||||||
| Default | Range | Max | Count | Total | Counted | ||||||
| Function | Biochemical Function | 0.5 | 0 - 2 | 2 | 2 |
1
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2 |
Waltes R et al. 2009 May (PMID:19409520); Stewart GS et al. 1999 Dec 10 (PMID:10612394);
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| 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);
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| Functional Alteration | Patient cells | 1 | 0 - 2 | 2 |
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| 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);
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| Cell culture model | 1 | 0 - 2 | |||||||||
| Rescue | Rescue in human | 2 | 0 - 4 |
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| 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 |
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| 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)*
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| CALCULATED CLASSIFICATION (DATE) |
Definitive
10/09/2018
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| EXPERT CURATION (DATE) |
Definitive
10/09/2018
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| EVIDENCE SUMMARY |
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.
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