GTS5:PALB2-related cancer predisposition syndrome (PALB2)

Genetic Tumour Syndromes (Who Classification, 5th ed.)

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Primary Author(s)*

Hieu Nguyen, PhD, FACMG

Parisa Kargaran, PhD

WHO Classification of Disease

Structure	Disease
Book	Genetic Tumour Syndromes (5th ed.)
Category	DNA repair and genomic stability
Family	Homologous recombination
Type	PALB2-related cancer predisposition syndrome (PALB2)
Subtype(s)	N/A

Related Terminology

	Acceptable		DNA double-strand break repair; homologous recombination repair; pancreatic cancer 3; Fanconi anaemia, complementation group N
	Primary Name		Partner and localizer of BRCA2 (PALB2)
	Synonyms		FANCN (Fanconi anemia when homozygous), FLJ21816
	Not Recommended		N/A

Definition/Description of Disease

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- Function: The PALB2 gene at 16p12.2 contains 13 exons encoding 1,186 amino acids. The PALB2 protein is a component of the homologous recombination complex machinery that binds to the BRCA2 protein to repair double-strand DNA breaks. PALB2 functions as a tumor-suppressor to maintain genome integrity.

- In the heterozygous state, germline pathogenic variants in PALB2 predispose carriers to several cancers, commonly including breast, pancreatic, and ovarian cancers, with incomplete penetrance for these cancers. Germline pathogenic variants in PALB2 have also been reported in individuals with prostate, gastric, and colon cancers.

- In the compound heterozygous or homozygous state, biallelic pathogenic variants in PALB2 cause Fanconi anemia (FA) subtype N (Complementation Group N - FANCN), which is a severe genomic instability condition characterized by growth retardation, congenital malformations, skeletal abnormalities, hearing loss, intellectual disability, progressive bone marrow failure, anemia, and pediatric cancer susceptibility (acute leukemia in early childhood).

- Incidence: 0.1%

- Heterozygous pathogenic variants in PALB2 are associated with a 33-53% risk for breast cancer and an increased risk for pancreatic and ovarian cancers.

- Lifetime risk of breast cancer in females is 35-60% (relative risk ~ 5-fold). The incidence of triple negative breast cancer is enriched in those with PALB2-related breast cancer.

PALB2 Related Cancer Predisposition Syndrome:

PALB2 encodes a key tumor suppressor protein that plays a central role in the homologous recombination (HR) DNA double strand break repair pathway, acting as a molecular scaffold that physically and functionally connects BRCA1 and BRCA2 . Loss of PALB2 function results in homologous recombination deficiency, leading to impaired RAD51 recruitment to sites of DNA damage, defective high fidelity DNA repair, and genomic instability molecular mechanisms shared with BRCA associated cancers .

Clinically, individuals with pathogenic PALB2 variants exhibit moderate to high penetrance for breast cancer, with cumulative lifetime risk estimates ranging from approximately 35–60%, depending on family history and modifying factors. In some families, breast cancer risks approach those observed in BRCA2 carriers. PALB2 associated breast cancers may present at younger ages than sporadic cases and encompass a range of histologic and molecular subtypes, including triple negative and hormone receptor positive tumors. An increased risk of male breast cancer has also been reported relative to the general population .

Beyond breast cancer, germline PALB2 pathogenic variants are associated with an increased risk of pancreatic ductal adenocarcinoma, and PALB2 is recognized as a clinically actionable pancreatic cancer susceptibility gene in multiple professional guidelines and consensus statements . Associations with ovarian cancer have been described, although penetrance appears lower than that observed for BRCA1 and BRCA2 .

Diagnostic Criteria:

The diagnosis of PALB2 related cancer predisposition syndrome is established by identifying a germline pathogenic or likely pathogenic variant in PALB2 using validated molecular genetic testing methods, including multigene hereditary cancer panels, genome sequencing, or targeted familial testing. Testing is typically pursued in individuals with early onset breast cancer, multiple primary malignancies, a personal or family history suggestive of hereditary breast and/or pancreatic cancer, or tumor genomic findings consistent with homologous recombination deficiency that prompt germline evaluation. Once a pathogenic variant is identified, cascade testing of at-risk relatives is recommended.

Differential Diagnosis:

The differential diagnosis includes other hereditary cancer predisposition syndromes involving defects in DNA damage response or homologous recombination repair pathways, particularly BRCA1 and BRCA2 related hereditary breast and ovarian cancer syndrome, CHEK2 associated cancer susceptibility, ATM associated hereditary cancer predisposition, and TP53 related Li-Fraumeni syndrome, especially in individuals with very early onset disease or multiple primary malignancies. Distinction among these conditions relies on germline genetic testing, tumor characteristics, and family history patterns.

Disease Context within WHO Classification:

Within the WHO Classification of Tumours, PALB2 related cancer predisposition syndrome is classified as a hereditary cancer susceptibility condition involving genes responsible for DNA repair and genome stability. PALB2 is discussed across WHO tumor classification volumes addressing breast, pancreatic, and gynecologic malignancies, where it is grouped with other high and moderate penetrance homologous recombination repair genes.

PALB2 associated cancers are classified according to tumor site and histopathology, rather than as a distinct morphologic entity. However, identification of the underlying genetic etiology has important implications for risk assessment, surveillance strategies, therapeutic decision making (including sensitivity to DNA damaging agents and PARP inhibitors), and familial counseling.

Genetic Abnormalities: Germline

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Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
PALB2	SNVs (frameshift, nonsense, canonical splice site, missense with loss of function, synonymous variants affecting splicing); CNVs (inactivating deletions or duplications).	Loss of function variants disrupt PALB2 mediated homologous recombination DNA repair through impaired BRCA1 BRCA2 interaction and defective RAD51 recruitment, resulting in homologous recombination deficiency and genomic instability.	Autosomal dominant cancer predisposition with moderate to high penetrance for breast cancer (~35-60%, modified by family history); Autosomal recessive inheritance causes Fanconi anemia, complementation group N (FA-N) with high penetrance.	Germline pathogenic variants are predominantly loss-of-function (frameshift, nonsense, splice site). Several founder mutations have been reported, including c.1592delT in Finnish populations and recurrent truncating variants in European ancestry cohorts. Missense variants are less common and require functional and/or segregation evidence for classification. CNVs involving partial or whole-gene deletions account for a minority of pathogenic alleles but are clinically significant. Biallelic pathogenic variants cause Fanconi anemia subtype N, characterized by childhood onset bone marrow failure, developmental anomalies, and early onset malignancies. PALB2 associated tumors share molecular features with BRCA-associated cancers and may demonstrate sensitivity to DNA damaging agents and PARP inhibitors.

Genetic Abnormalities: Somatic

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Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
PALB2	Biallelic inactivation (second hit): loss of heterozygosity (LOH), somatic truncating mutation, focal or whole-gene deletion, copy-neutral LOH	Somatic inactivation of the remaining wild-type PALB2 allele in tumors from germline carriers leads to complete loss of PALB2 function, resulting in homologous recombination deficiency, impaired RAD51 loading, and genomic instability	Not inherited; somatic event occurring in tumors of germline carriers; contributes to tumor initiation and progression	Tumor development in PALB2 associated cancers typically follows a two hit model, analogous to BRCA1/2, with somatic loss of the wild-type allele frequently observed in breast and pancreatic tumors . Biallelic loss is associated with HR-deficient genomic signatures and therapeutic sensitivity to DNA-damaging agents and PARP inhibitors
EXAMPLE: BRCA1	EXAMPLE: Reversion mutation	EXAMPLE: After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

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Additional Information

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Links

https://www.ncbi.nlm.nih.gov/clinvar/?term=%22PALB2%22%5BGENE%5D&redir=gene

References

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Xia B, Sheng Q, Nakanishi K, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Molecular Cell. 2006;22(6):719–729.

Sy SMH, Huen MSY, Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proceedings of the National Academy of Sciences USA. 2009;106(17):7155–7160.

Park JY, Zhang F, Andreassen PR. PALB2: the hub of a network of tumor suppressors involved in DNA damage responses. Biochimica et Biophysica Acta. 2014;1846(1):263–275.

Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. New England Journal of Medicine. 2014;371(6):497–506.

Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology. 2017;3(9):1190–1196.

Yang X, Leslie G, Doroszuk A, et al. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. Journal of Clinical Oncology. 2020;38(7):674–685.

Heikkinen T, Kärkkäinen H, Aaltonen K, et al. The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Cancer Research. 2009;69(3):862–868.

Hu C, Hart SN, Polley EC, et al. Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients. JAMA. 2018;319(23):2401–2409.

National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Current version.

International Agency for Research on Cancer (IARC). WHO Classification of Tumours. Genetic tumour syndromes and DNA repair–related cancer susceptibility.

Notes

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