Gene Validity Curation

PALB2 - Fanconi anemia complementation group N

Gene: PALB2 (HGNC:26144)
Classification - 08/18/2019
Disease: Fanconi anemia complementation group N (MONDO_0012565)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer GCEP
Evidence Summary: There is abundant evidence published associating the PALB2 gene with Fanconi anemia complementation group N, since the gene-disease relationship was first proposed by Xia et al. (2007). Multiple case level studies have been performed with FA patients that have variants in the PALB2 gene. A significant amount of case-level data is available, however the maximum points for genetic evidence has been reached (12 points). BRCA1, BRCA2, BRIP1 and RAD51C have also been established as FA genes in the FA/BRCA DNA repair pathway. No full length PALB2 protein was detected in patient (EUFA1341)'s lymphoblasts and fibroblasts. The patients cells also show hypersensitivity to cross-linking agents and lacked BRCA2. Palb2-/-mouse model have been established to show consistent phenotypes with FA patients and Brca1 and Brca2 knockout mice including mesoderm differentiation defect and early embryonic lethality. Introduction of wild-type PALB2 into EUFA1341 fibroblasts cells normalized the association of BRCA2 with the chromatin/nuclear matrix fraction, the ability to form Rad51 foci and the sensitivity to MMC. PALB2 ∆ChAM did not rescue the sensitivity phenotype. All of these types of evidence are consistent with a definitive relationship between the PALB2 gene and Fanconi anemia complementation group N.
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 6
12
12
Xia B et al. 2007 Feb (PMID:17200672); Reid S et al. 2007 Feb (PMID:17200671);
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 1
2
2
Nalepa G et al. 2018 Mar (PMID:29376519);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Xia B et al. 2007 Feb (PMID:17200672);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Xia B et al. 2007 Feb (PMID:17200672);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1 3
Rantakari P et al. 2010 Aug 1 (PMID:20484223);
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 2 2
Xia B et al. 2007 Feb (PMID:17200672); Bleuyard JY et al. 2012 Feb 1 (PMID:22193777);
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 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)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
04/19/2019
EXPERT CURATION (DATE)
Definitive
08/18/2019
EVIDENCE SUMMARY
There is abundant evidence published associating the PALB2 gene with Fanconi anemia complementation group N, since the gene-disease relationship was first proposed by Xia et al. (2007). Multiple case level studies have been performed with FA patients that have variants in the PALB2 gene. A significant amount of case-level data is available, however the maximum points for genetic evidence has been reached (12 points). BRCA1, BRCA2, BRIP1 and RAD51C have also been established as FA genes in the FA/BRCA DNA repair pathway. No full length PALB2 protein was detected in patient (EUFA1341)'s lymphoblasts and fibroblasts. The patients cells also show hypersensitivity to cross-linking agents and lacked BRCA2. Palb2-/-mouse model have been established to show consistent phenotypes with FA patients and Brca1 and Brca2 knockout mice including mesoderm differentiation defect and early embryonic lethality. Introduction of wild-type PALB2 into EUFA1341 fibroblasts cells normalized the association of BRCA2 with the chromatin/nuclear matrix fraction, the ability to form Rad51 foci and the sensitivity to MMC. PALB2 ∆ChAM did not rescue the sensitivity phenotype. All of these types of evidence are consistent with a definitive relationship between the PALB2 gene and Fanconi anemia complementation group N.