PALB2
partner and localizer of BRCA2, the group of WD repeat domain containing|FA complementation groups
Basic information
Region (hg38): 16:23603160-23641321
Links
Phenotypes
GenCC
Source:
- Fanconi anemia complementation group N (Definitive), mode of inheritance: AR
- pancreatic cancer, susceptibility to, 3 (Strong), mode of inheritance: AD
- Fanconi anemia complementation group N (Strong), mode of inheritance: AR
- hereditary breast carcinoma (Definitive), mode of inheritance: AD
- Fanconi anemia (Supportive), mode of inheritance: AR
- Fanconi anemia complementation group N (Strong), mode of inheritance: AR
- pancreatic cancer, susceptibility to, 3 (Strong), mode of inheritance: AD
- hereditary nonpolyposis colon cancer (Limited), mode of inheritance: AD
- hereditary breast carcinoma (Definitive), mode of inheritance: AD
- familial ovarian cancer (Moderate), mode of inheritance: AD
- Fanconi anemia complementation group N (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Breast-ovarian cancer, familial, susceptibility to, 5; Pancreatic cancer, susceptibility to 3; Fanconi anemia, complementation group N | AD/AR | Allergy/Immunology/Infectious; Cardiovascular; Hematologic; Oncologic | 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 | Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Renal | 17200668; 17287723; 17200671; 17200672; 19264984; 20858716; 22241545; 20301575; 23448497; 25099575; 31841383 |
ClinVar
This is a list of variants' phenotypes submitted to
- Familial cancer of breast (762 variants)
- Hereditary cancer-predisposing syndrome (424 variants)
- not provided (146 variants)
- Hereditary breast ovarian cancer syndrome (31 variants)
- Malignant tumor of breast (18 variants)
- Gastric cancer (16 variants)
- Fanconi anemia complementation group N (14 variants)
- PALB2-related disorder (12 variants)
- Breast and/or ovarian cancer (10 variants)
- Breast-ovarian cancer, familial, susceptibility to, 5 (9 variants)
- Breast cancer, susceptibility to (7 variants)
- Familial cancer of breast;Fanconi anemia complementation group N;Pancreatic cancer, susceptibility to, 3 (6 variants)
- Pancreatic cancer, susceptibility to, 3;Familial cancer of breast;Fanconi anemia complementation group N (5 variants)
- Breast-ovarian cancer, familial, susceptibility to, 1 (5 variants)
- Familial cancer of breast;Pancreatic cancer, susceptibility to, 3;Fanconi anemia complementation group N (5 variants)
- Breast neoplasm (5 variants)
- not specified (4 variants)
- Breast carcinoma (4 variants)
- Cancer of the pancreas (2 variants)
- Pancreatic cancer, susceptibility to, 3 (2 variants)
- Breast cancer, susceptibility to;Pancreatic cancer, susceptibility to, 3 (2 variants)
- Breast-ovarian cancer, familial, susceptibility to, 5;Pancreatic cancer, susceptibility to, 3 (1 variants)
- Carcinoma of pancreas (1 variants)
- Colorectal cancer (1 variants)
- Fanconi anemia complementation group N;Familial cancer of breast;Pancreatic cancer, susceptibility to, 3 (1 variants)
- Lynch syndrome 1 (1 variants)
- Inherited ovarian cancer (without breast cancer) (1 variants)
- Neuroendocrine tumor of pancreas (1 variants)
- Inherited breast cancer and ovarian cancer (1 variants)
- Inherited prostate cancer (1 variants)
- NICE approved PARP inhibitor treatment (1 variants)
- Carcinoma of colon (1 variants)
- Malignant tumor of breast;Fanconi anemia complementation group N (1 variants)
- Family history of cancer;Neoplasm of uterus (1 variants)
- Fanconi anemia complementation group N;Pancreatic cancer, susceptibility to, 3;Malignant tumor of breast (1 variants)
- Colonic neoplasm (1 variants)
- Familial cancer of breast;Hereditary cancer-predisposing syndrome (1 variants)
- Precursor B-cell acute lymphoblastic leukemia (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the PALB2 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 15 | 891 | 907 | |||
| missense | 2353 | 27 | 2387 | |||
| nonsense | 207 | 77 | 285 | |||
| start loss | 5 | |||||
| frameshift | 660 | 161 | 825 | |||
| inframe indel | 67 | 68 | ||||
| splice donor/acceptor (+/-2bp) | 85 | 96 | ||||
| splice region | 8 | 71 | 78 | 157 | ||
| non coding | 11 | 116 | 264 | 30 | 424 | |
| Total | 884 | 331 | 2565 | 1182 | 35 |
Highest pathogenic variant AF is 0.000125
Variants in PALB2
This is a list of pathogenic ClinVar variants found in the PALB2 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 16-23603227-C-A | Familial cancer of breast • Fanconi anemia complementation group N | Uncertain significance (Jan 13, 2018) | ||
| 16-23603444-T-C | Hereditary cancer-predisposing syndrome | Uncertain significance (Aug 31, 2018) | ||
| 16-23603446-ACTTTACC-TGAATAGTGGTATACAAATT | Hereditary cancer-predisposing syndrome | Likely benign (Jan 17, 2017) | ||
| 16-23603447-CTTTACCCTAACTTATGAATAG-C | Hereditary cancer-predisposing syndrome | Uncertain significance (Apr 19, 2021) | ||
| 16-23603449-T-A | Hereditary cancer-predisposing syndrome | Uncertain significance (Dec 13, 2018) | ||
| 16-23603455-T-C | Hereditary cancer-predisposing syndrome | Uncertain significance (Aug 21, 2015) | ||
| 16-23603457-A-C | Hereditary cancer-predisposing syndrome | Likely benign (Jun 28, 2016) | ||
| 16-23603456-AACTTATGAATAGTGGTATACAAATATATTTCCATCTTTTTGTCCAGCCAGCAAATGAGAGTCTGTACCCGACCATTTCACAAAAGACCAATGTTGGTCAGAGACAGGTGGGAGGAGGGCAGTACACTGACCGAGAAGTAAGTCCCAAATGGCAATTGTTCCAGAAGTCAAGATTGCTGCTGCACAGTGATCTTTCACGTCACCTTCCAGGAACCTGATAGCATACAAAGAAGATATAATTCAGATTACATATCCAAAAAACAATTAAAAAAAAAAAAAAGGTCAAAACCATGTTCCCAAAACCAGCAACAGGAACAAAAATCCCTGTAACTATGAATGCCTACATTTGTAGCCTTAGAGGTCT-A | Malignant tumor of breast | Likely pathogenic (-) | ||
| 16-23603461-A-G | Familial cancer of breast • Hereditary cancer-predisposing syndrome | Uncertain significance (Aug 18, 2023) | ||
| 16-23603462-T-C | Familial cancer of breast • Hereditary cancer-predisposing syndrome | Likely benign (Sep 15, 2023) | ||
| 16-23603463-G-C | Familial cancer of breast | Uncertain significance (Dec 29, 2020) | ||
| 16-23603463-G-GAATAGTGGT | Hereditary cancer-predisposing syndrome | Uncertain significance (Apr 18, 2022) | ||
| 16-23603465-A-G | Hereditary cancer-predisposing syndrome | Likely benign (Sep 13, 2022) | ||
| 16-23603467-A-C | not specified • Familial cancer of breast • Hereditary cancer-predisposing syndrome | Uncertain significance (Oct 14, 2020) | ||
| 16-23603467-A-G | Familial cancer of breast • Hereditary cancer-predisposing syndrome | Uncertain significance (Nov 24, 2023) | ||
| 16-23603468-G-C | Uncertain significance (Aug 25, 2018) | |||
| 16-23603468-GT-G | Hereditary cancer-predisposing syndrome • Familial cancer of breast | Uncertain significance (Apr 19, 2021) | ||
| 16-23603470-G-A | Hereditary cancer-predisposing syndrome | Uncertain significance (May 17, 2019) | ||
| 16-23603470-G-T | Uncertain significance (May 04, 2023) | |||
| 16-23603471-G-A | Uncertain significance (Aug 25, 2018) | |||
| 16-23603471-G-C | Fanconi anemia complementation group N • Breast cancer, susceptibility to • Familial cancer of breast • not specified • Hereditary cancer-predisposing syndrome • Pancreatic cancer, susceptibility to, 3 • PALB2-related disorder | Pathogenic/Likely pathogenic (Oct 10, 2024) | ||
| 16-23603471-G-T | Hereditary cancer-predisposing syndrome • Familial cancer of breast • Hereditary breast ovarian cancer syndrome • Familial cancer of breast;Fanconi anemia complementation group N;Pancreatic cancer, susceptibility to, 3 • Breast-ovarian cancer, familial, susceptibility to, 1 • PALB2-related disorder | Pathogenic (Apr 05, 2023) | ||
| 16-23603473-A-C | Familial cancer of breast • Hereditary cancer-predisposing syndrome | Uncertain significance (Apr 09, 2018) | ||
| 16-23603473-ATACAAATATA-CTACATT | Familial cancer of breast | Pathogenic (Oct 02, 2023) | ||
| 16-23603474-T-C | Familial cancer of breast • Hereditary cancer-predisposing syndrome | Likely benign (Dec 04, 2019) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| PALB2 | protein_coding | protein_coding | ENST00000261584 | 13 | 38144 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 3.04e-19 | 0.204 | 125694 | 0 | 54 | 125748 | 0.000215 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 0.276 | 568 | 587 | 0.968 | 0.0000295 | 7797 |
| Missense in 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 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000579 | 0.000579 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000272 | 0.000272 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.000275 | 0.000273 |
| Middle Eastern | 0.000272 | 0.000272 |
| South Asian | 0.000229 | 0.000229 |
| Other | 0.00 | 0.00 |
dbNSFP
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.;
- Pathway
- 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;Homology Directed Repair;Fanconi anemia pathway;Homologous DNA Pairing and Strand Exchange;Resolution of D-loop Structures through Holliday Junction Intermediates;Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA);Resolution of D-Loop Structures;HDR through Homologous Recombination (HRR)
(Consensus)
Recessive Scores
- pRec
- 0.279
Intolerance Scores
- loftool
- 0.965
- rvis_EVS
- 0.32
- rvis_percentile_EVS
- 72.85
Haploinsufficiency Scores
- pHI
- 0.164
- hipred
- Y
- hipred_score
- 0.565
- ghis
- 0.565
Essentials
- essential_gene_CRISPR
- E
- essential_gene_CRISPR2
- S
- essential_gene_gene_trap
- E
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.903
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Palb2
- Phenotype
- integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; neoplasm; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan);
Gene ontology
- Biological process
- double-strand break repair via homologous recombination;somitogenesis;inner cell mass cell proliferation;mesoderm development;animal organ morphogenesis;multicellular organism growth;post-anal tail morphogenesis;negative regulation of apoptotic process;embryonic organ development
- Cellular component
- nucleoplasm
- Molecular function
- DNA binding;protein binding