PALB2
protein-codingpartner and localizer of BRCA2, the group of WD repeat domain containing|FA complementation groups
Gene summary
This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~38.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0700272
Submitter: ClinGen
PALB2 encodes a protein that directly interacts with BRCA2. PALB2 was first reported in relation to autosomal dominant PALB2-related cancer predisposition in 2007 (Rahman et al., PMID: 17200668). PALB2-related cancer predisposition is characterized by a susceptibility to breast, ovarian, and pancreatic cancers. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern and phenotypic variability. Therefore, breast, ovarian, and pancreatic cancers have been lumped into this curation for the new disease entity MONDO:0700272 and the prior separate curations for hereditary breast and ovarian cancer and hereditary nonpolyposis colon cancer replaced by this updated curation. Fanconi anemia complementation group N (MONDO:0012565), an autosomal recessive disorder with unique clinical features was curated separately. The mechanism of disease is loss of function. Seventeen variants (nonsense, frameshift, large deletion, and missense) that have been reported in 17 probands in 8 publications (PMIDs: 17200668, 17420451, 30875412, 31858328, 28767289, 19264984, 30322717, 29053726) are included in this curation. In addition, several case-control studies have been curated which support the association of breast, ovarian, and pancreatic cancers with PALB2-related cancer predisposition (PMIDs: 26720728, 28888541, 33471974, 33471991, 29922827). More evidence is available in the literature, but the maximum score for genetic evidence (12 Points) has been reached. Please note, at least one case-control study supports an association of gastric cancer with PALB2-related cancer predisposition, but overall evidence for this association is still limited (PMID: 36988593). In addition, the association of PALB2 with colorectal cancer susceptibility was evaluated, and no significant evidence was found to support this gene-disease association (PMIDs: 33309985, 31841383). PALB2-related cancer predisposition is also supported by experimental evidence, including in vitro functional assays and animal models (4 Points, PMIDs: 31636395, 19369211, 19423707, 16793542, 33893322). This experimental evidence demonstrates that variants causing loss of function result in impaired interaction with BRCA2 and homologous recombination deficiencies. In summary, there is definitive evidence supporting the relationship between PALB2 and autosomal dominant PALB2-related cancer predisposition. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was evaluated as definitive for cancer predisposition by the Hereditary Cancer GCEP on 12/15/2023. Information regarding the colon cancer gene-disease association was evaluated on 5/24/2024 and approved by the ClinGen Hereditary Cancer GCEP (SOP Version 10). As a result of this re-evaluation, the overall classification for Definitive did not change for hereditary breast and ovarian cancer but were lumped into this new entity and HNPCC curation previously Limited was removed as data was no longer scorable.
Inheritance Pattern: AR
Disease ID:MONDO:0012565
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012565
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012565
Submitter: ClinGen
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.
Inheritance Pattern: AD
Disease ID:MONDO:0013236
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0019391
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0016419
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012565
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013236
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Renal
Intervention: Allergy/Immunology/Infectious; Cardiovascular; Hematologic; Oncologic
Rationale: For Fanconi anemia, specific treatments can help manifestations (eg, oral androgens for blood counts; G-CSF for neutrophil count), and awareness of the possibility of congenital anomalies (eg, cardiac anomalies) may help enable identification and management; HSCT can be curative, but solid tumor risk may remain; surveillance for complications such as bone marrow failure is recommended; For pancreatic and breast/ovarian cancer, surveillance and early treatment may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PALB2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024675.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 5 | 22 | 1100 | 105 | 1234 |
| missense | 42 | 20 | 2721 | 485 | 14 | 3282 |
| nonsense | 251 | 81 | 2 | 334 | ||
| start loss | 2 | 8 | 10 | |||
| frameshift | 795 | 215 | 9 | 1019 | ||
| splice donor/acceptor (+/-2bp) | 9 | 121 | 12 | 1 | 143 | |
| Total | 1101 | 450 | 2766 | 1586 | 119 | 6022 |
Highest pathogenic variant AF is 0.00020838481
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_078951.2 | 13 | MANE Select | |
| Ensembl | ENSP00000261584.4 | 13 | MANE Select | |
| RefSeq | NP_001394225.1 | 12 | Standard | |
| RefSeq | NP_001394226.1 | 12 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fanconi anemia pathway - Homo sapiens (human)
- Homologous recombination - Homo sapiens (human)
- HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
- DNA Repair
- DNA Double-Strand Break Repair
Biological Process
- double-strand break repair via homologous recombination
- somitogenesis
- inner cell mass cell proliferation
- mesoderm development
- animal organ morphogenesis
Molecular Function
- DNA binding
- protein binding
Cellular Component
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261584
- Coding exons
- 13
- Length
- 38144
- Individuals with no LoFs
- 125694
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 54
- Defined
- 125748
- p
- 0.000215
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.276 | 568 | 587 | 0.968 | 0.0000295 | 7797 |
| Missense (PolyPhen) | 142 | 139.27 | 1.0196 | 1939 | ||
| Synonymous | -0.733 | 237 | 223 | 1.06 | 0.0000125 | 2293 |
| Loss of Function | 1.52 | 35 | 46.1 | 0.759 | 0.00000229 | 629 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00049 | 0.00049 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00027 | 0.00027 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks (PubMed:16793542, PubMed:19423707, PubMed:19369211, PubMed:22941656, PubMed:24141787, PubMed:28319063). Strongly stimulates the DNA strand-invasion activity of RAD51, stabilizes the nucleoprotein filament against a disruptive BRC3-BRC4 polypeptide and helps RAD51 to overcome the suppressive effect of replication protein A (RPA) (PubMed:20871615). Functionally cooperates with RAD51AP1 in promoting of D-loop formation by RAD51 (PubMed:20871616). Serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex which is essential for homologous recombination (PubMed:19369211). Via its WD repeats is proposed to scaffold a HR complex containing RAD51C and BRCA2 which is thought to play a role in HR-mediated DNA repair (PubMed:24141787). Essential partner of BRCA2 that promotes the localization and stability of BRCA2 (PubMed:16793542). Also enables its recombinational repair and checkpoint functions of BRCA2 (PubMed:16793542). May act by promoting stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation (PubMed:16793542). Binds DNA with high affinity for D loop, which comprises single- stranded, double-stranded and branched DNA structures (PubMed:20871616). May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with BRCA2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity (PubMed:24485656). {ECO:0000269|PubMed:16793542, ECO:0000269|PubMed:19369211, ECO:0000269|PubMed:19423707, ECO:0000269|PubMed:20871615, ECO:0000269|PubMed:20871616, ECO:0000269|PubMed:22941656, ECO:0000269|PubMed:24141787, ECO:0000269|PubMed:24485656, ECO:0000269|PubMed:28319063}.;
- Disease
- DISEASE: Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:17287723, ECO:0000269|PubMed:22241545, ECO:0000269|PubMed:28319063}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Breast cancer susceptibility is strongly associated with PALB2 truncating mutations. Conversely, rare missense mutations do not strongly influence breast cancer risk (PubMed:22241545). {ECO:0000269|PubMed:22241545}.; DISEASE: Fanconi anemia complementation group N (FANCN) [MIM:610832]: A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. {ECO:0000269|PubMed:17200672}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pancreatic cancer 3 (PNCA3) [MIM:613348]: A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. {ECO:0000269|PubMed:19264984}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.279
Intolerance Scores
- LoFtool
- 0.965
- RVIS EVS
- 0.32
- RVIS percentile EVS
- 72.85
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.903
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |