Alt. symbols: FLJ21816 | FANCN

Approved name: partner and localizer of BRCA2
Alt. names: Fanconi anemia, complementation group N

Location: 16p12.2: 23603160 - 23641321 (-)
Gene type: protein_coding, 19 transcripts.

Scores: LoFtool: 0.965000 | pLI: 0.00000000 | LOEUF: 1.006

HGNC: 26144

NCBI: 79728, RefSeq: NG_007406.1

Ensembl: ENSG00000083093.12

LRG_308 | Status: public

OMIM: 610355

Expression | ProteinAtlas

PALB2 plays a critical role in homologous recombination (HR)-based repair mechanisms through its ability to recruit BRCA2 and RAD51 to DNA breaks (PMID: 16793542, 19423707, 19369211, 22941656, 24141787, 28319063). Via its WD repeats, it serves as a molecular scaffold for the formation of the BRCA1-PALB2-BRCA2 complex essential for HR-based repair (PMID: 19369211, 24141787). By facilitating the localization and stable association of BRCA2 with nuclear structures, PALB2 enables both its HR and checkpoint functions (PMID: 16793542, 16793542, 16793542). PALB2 also shows high affinity for D loops and functionally cooperates with RAD51AP1 to promote D-loop formation by RAD51 (PMID: 20871616, 20871616).

Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function (LOF) variants in PALB2 are known to be pathogenic in both heterozygous and homozygous states (PMID: 17200668, 24136930, 25099575). Biallelic PALB2 LOF mutations cause Fanconi anemia (FA), complementation group N [MIM:610832], and, similar to biallelic BRCA2 mutations, confer a high risk of childhood cancer (PMID: 17200671). FA is a multi-system syndrome featuring a broad s pectrum of congenital anomalies in addition to bone marrow failure and increased risk for malignancy. Physical abnormalities are present in ~75% and include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, while the incidence of acute myeloid leukemia (AML) is 13% by age 50. Moreover, due to the involvement of FA genes in key DNA repair pathways, these individuals are also at increased risk for solid tumors – particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract. Monoallelic loss-of-function PALB2 mutations (often nonsense or frameshift) confer adult susceptibility to breast cancer [MIM:114480] and pancreatic cancer [MIM:613348] and have been implicated in susceptibility to other solid tumors such as prostate (PMID: 17287723) and gastric (PMID: 28024868). In additional to these germline changes, somatic PALB2 variants have been reported for diverse cancers. Of note, while digenic causes of FA have been proposed (PMID: 33224012; Murad et al. AJMB 2019), the combination of PALB2/FANCN and FANCI mutations has thus far not been described. [Load More]