PALB2

partner and localizer of BRCA2, the group of WD repeat domain containing|FA complementation groups

Basic information

Region (hg38): 16:23603159-23641321

Links

ENSG00000083093 ∙ NCBI:79728 ∙ OMIM:610355 ∙ HGNC:26144 ∙ Uniprot:Q86YC2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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: CGD

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 ClinVar and linked to the PALB2 gene.

• Familial cancer of breast (4162 variants)
• Hereditary cancer-predisposing syndrome (3358 variants)
• not provided (1165 variants)
• not specified (530 variants)
• Hereditary breast ovarian cancer syndrome (116 variants)
• Fanconi anemia complementation group N (113 variants)
• Malignant tumor of breast (107 variants)
• Breast and/or ovarian cancer (86 variants)
• Familial cancer of breast;Fanconi anemia complementation group N;Pancreatic cancer, susceptibility to, 3 (74 variants)
• Breast-ovarian cancer, familial, susceptibility to, 5 (58 variants)
• Pancreatic cancer, susceptibility to, 3;Familial cancer of breast;Fanconi anemia complementation group N (44 variants)
• PALB2-related condition (39 variants)
• Fanconi anemia complementation group N;Pancreatic cancer, susceptibility to, 3;Familial cancer of breast (31 variants)
• Familial cancer of breast;Pancreatic cancer, susceptibility to, 3;Fanconi anemia complementation group N (28 variants)
• Pancreatic cancer, susceptibility to, 3 (26 variants)
• Carcinoma of colon (23 variants)
• Fanconi anemia complementation group N;Familial cancer of breast;Pancreatic cancer, susceptibility to, 3 (22 variants)
• Gastric cancer (22 variants)
• PALB2-Related Disorders (15 variants)
• Breast cancer, susceptibility to (9 variants)
• Pancreatic cancer, susceptibility to, 3;Fanconi anemia complementation group N;Familial cancer of breast (9 variants)
• Familial ovarian cancer (8 variants)
• Ovarian cancer (7 variants)
• Breast-ovarian cancer, familial, susceptibility to, 1 (7 variants)
• Endometrial carcinoma (6 variants)
• Breast carcinoma (6 variants)
• Chordoma (6 variants)
• Breast neoplasm (6 variants)
• Hereditary cancer (5 variants)
• Breast cancer, susceptibility to;Pancreatic cancer, susceptibility to, 3 (4 variants)
• Hereditary cancer-predisposing syndrome;Fanconi anemia complementation group N (3 variants)
• Colorectal cancer (3 variants)
• Inborn genetic diseases (3 variants)
• Pancreatic cancer, susceptibility to, 3;Breast cancer, susceptibility to (3 variants)
• Familial cancer of breast;Hereditary cancer-predisposing syndrome (3 variants)
• Fanconi anemia (2 variants)
• See cases (2 variants)
• Diffuse midline glioma, H3 K27-altered (2 variants)
• - (2 variants)
• BAP1-related tumor predisposition syndrome (2 variants)
• Cancer of the pancreas (2 variants)
• Lynch syndrome 1 (2 variants)
• Neoplasm of ovary (2 variants)
• Hereditary cancer-predisposing syndrome;Familial cancer of breast (1 variants)
• Lung cancer (1 variants)
• Uterine corpus cancer (1 variants)
• Fanconi anemia;Hereditary cancer (1 variants)
• bilateral breast cancer (1 variants)
• Bile duct cancer (1 variants)
• Fanconi anemia complementation group N;Pancreatic cancer, susceptibility to, 3;Malignant tumor of breast (1 variants)
• Fanconi anemia complementation group N;Pancreatic cancer, susceptibility to, 3;Breast-ovarian cancer, familial, susceptibility to, 5 (1 variants)
• Colonic neoplasm (1 variants)
• Retinoblastoma (1 variants)
• Carcinoma of pancreas (1 variants)
• Ovarian carcinoma (1 variants)
• Neuroendocrine tumor of pancreas (1 variants)
• Familial cancer of breast;Fanconi anemia complementation group N;Familial ovarian cancer (1 variants)
• Triple-negative breast cancer (1 variants)
• Infiltrating duct carcinoma of breast (1 variants)
• Fanconi anemia complementation group N;Malignant tumor of breast (1 variants)
• Familial cancer of breast;Hereditary cancer-predisposing syndrome;Fanconi anemia complementation group N (1 variants)
• Familial cancer of breast;Fanconi anemia complementation group N;Pancreatic cancer, susceptibility to, 3;Tracheoesophageal fistula (1 variants)
• Family history of cancer;Neoplasm of uterus (1 variants)
• Pancreatic cancer, susceptibility to, 3;Familial cancer of breast (1 variants)
• Anaplastic ependymoma (1 variants)
• Pilocytic astrocytoma (1 variants)
• Hereditary breast cancer (1 variants)
• PALB2-related disorder (1 variants)
• Generalized hypopigmentation;Basal cell carcinoma (1 variants)
• B lymphoblastic leukemia lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) (1 variants)
• Precursor B-cell acute lymphoblastic leukemia (1 variants)
• Papillary thyroid carcinoma (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		1	18	851		870
missense	1	1	2285	20	5	2312
nonsense	206	70	1			277
start loss		3	1			4
frameshift	639	153	4			796
inframe indel			61			61
splice donor/acceptor (+/-2bp)	4	85	7			96
splice region		8	71	72		151
non coding	11	3	108	252	27	401
Total	861	316	2485	1123	32

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		Hereditary cancer-predisposing syndrome • Familial cancer of breast	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)
16-23603471-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 (Jan 24, 2024)
16-23603471-G-T		Hereditary cancer-predisposing syndrome • Familial cancer of breast • Hereditary breast ovarian cancer syndrome • Familial cancer of breast;Pancreatic cancer, susceptibility to, 3;Fanconi anemia complementation group N • 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)
16-23603475-A-G		Hereditary cancer-predisposing syndrome • Familial cancer of breast	Uncertain significance (Dec 05, 2023)

GnomAD

Source: gnomAD

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: dbNSFP

• 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