GTS5:PALB2-related cancer predisposition syndrome (PALB2)

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

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Primary Author(s)*

Hieu Nguyen, Ph.D., FACMG

Parisa Kargaran, Ph.D.

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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PALB2 – Gene Function and Clinical Relevance

Gene Function

The PALB2 gene is located at chromosome 16p12.2 and contains 13 exons, encoding a 1,186 amino acid protein. PALB2 (Partner and Localizer of BRCA2) is a key component of the homologous recombination (HR) DNA repair pathway, where it directly interacts with BRCA2 to facilitate the accurate repair of DNA double-strand breaks. Through its role in DNA damage repair, PALB2 functions as a tumor suppressor that maintains genomic integrity

Clinical Phenotypes by Zygosity

Heterozygous State (Monoallelic Pathogenic Variants)

Germline heterozygous pathogenic variants in PALB2 confer susceptibility to hereditary cancer syndromes with incomplete penetrance. The most frequently associated malignancies include breast, pancreatic, and ovarian cancers. Germline PALB2 pathogenic variants have also been reported in individuals with prostate, gastric, and colorectal cancers, though penetrance for these cancers is less well established.

Cancer risk estimates for heterozygous carriers:

• Lifetime breast cancer risk (females): ~35–60%

• Relative risk: ~5-fold compared with the general population

• Tumor phenotype: Enrichment of triple-negative breast cancer among PALB2-associated breast cancers

Biallelic State (Compound Heterozygous or Homozygous Pathogenic Variants)

Biallelic pathogenic variants in PALB2 result in Fanconi anemia subtype N (FANCN), a severe genomic instability disorder characterized by growth retardation, congenital malformations, skeletal abnormalities, hearing loss, intellectual disability, progressive bone marrow failure, anemia, and increased susceptibility to pediatric cancers, particularly acute leukemia in early childhood.

Incidence

The estimated population frequency of pathogenic PALB2 variants is approximately 0.1% .

Summary of Cancer Risks in Heterozygous Carriers

Heterozygous pathogenic variants in PALB2 are associated with:

• Breast cancer risk: ~33–53%, with some studies estimating risks up to 60%

• Pancreatic cancer risk: Increased relative to the general population

• Ovarian cancer risk: Moderately increased

• Breast cancer subtype: Enrichment of triple-negative 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
PALB2	Somatic loss of function variants (frameshift, nonsense, splice site) in sporadic tumors	Somatic PALB2 loss disrupts HR DNA repair independently of germline status, resulting in HR-deficient tumor phenotypes.	Somatic, non-heritable; variable expressivity depending on tumor type and co-occurring alterations	Somatic PALB2 alterations are less frequent than BRCA1/2 alterations but have been identified in breast, pancreatic, and other solid tumors. Tumors may demonstrate “BRCAness” features and potential responsiveness to HR-directed therapies.
PALB2	Reversion mutations (therapy associated)	Secondary somatic mutations restore the open reading frame or functional domains of PALB2, partially or fully rescuing homologous recombination activity	Acquired somatic resistance mechanism; observed after selective therapeutic pressure	Reversion mutations have been reported in PALB2 deficient tumors following treatment with PARP inhibitors or platinum based chemotherapy, leading to restoration of HR repair and acquired therapeutic resistance, similar to mechanisms described for BRCA1/2

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
PALB2; Loss of function germline variants (frameshift, nonsense, splice site, deletions)	Homologous recombination (HR) DNA double-strand break repair	Disruption of PALB2-mediated BRCA1–BRCA2 complex formation leads to impaired RAD51 recruitment, defective high fidelity DNA repair, homologous recombination deficiency, and genomic instability, promoting tumor initiation and progression
PALB2; Biallelic inactivation (germline + somatic second hit)	DNA damage response and genome stability maintenance	Complete loss of PALB2 function results in profound HR deficiency (“BRCAness”), accumulation of chromosomal aberrations, and increased sensitivity to DNA-damaging agents and PARP inhibition
PALB2; Biallelic germline variants	Fanconi anemia (FA) pathway / interstrand crosslink repair	Failure of FA pathway coordination causes Fanconi anemia complementation group N, characterized by bone marrow failure, developmental abnormalities, and early-onset malignancies
PALB2; Reversion mutations (therapy-associated)	Restoration of homologous recombination repair	Secondary somatic mutations restore PALB2 reading frame or function, reactivating HR repair and leading to resistance to PARP inhibitors and platinum-based chemotherapy

Genetic Diagnostic Testing Methods

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Recommended testing approaches for PALB2 include comprehensive germline sequencing with concurrent copy number analysis. Next generation sequencing (NGS) based multigene hereditary cancer panels or targeted PALB2 sequencing are the primary diagnostic methods to identify clinically significant variants, including pathogenic single-nucleotide variants (SNVs), small insertions/deletions (indels), and canonical splice-site alterations. Because exonic and whole gene deletions or duplications represent a clinically relevant subset of pathogenic PALB2 variants, copy number variant (CNV) analysis should be performed as part of routine testing. CNV detection may be achieved using NGS read-depth algorithms, multiplex ligation dependent probe amplification (MLPA), or chromosomal microarray (CMA) when appropriate. For individuals with a strong personal or family history suggestive of hereditary breast, ovarian, or pancreatic cancer and negative standard testing, RNA analysis may be considered to clarify the functional impact of suspected splice-altering variants or deep intronic changes . When PALB2 variants are identified through tumor only genomic testing, paired germline testing is recommended to distinguish germline pathogenic variants from somatic alterations and to inform clinical management, cascade testing, and cancer risk assessment for at-risk relatives.

Additional Information

Pathogenic variants in PALB2 are associated with hereditary breast cancer susceptibility and confer a moderate to high lifetime risk of breast cancer, with risk estimates approaching those observed for BRCA2 in some families. Female carriers have an estimated 35–58% lifetime risk of breast cancer by age 70, with risk modified by family history and other genetic or environmental factors. PALB2 pathogenic variants are also associated with an increased risk of pancreatic cancer, and emerging evidence suggests a possible association with ovarian cancer, although penetrance for non-breast cancers remains lower and less well defined compared with BRCA1/2. Biallelic pathogenic variants in PALB2 cause Fanconi anemia subtype N, characterized by congenital anomalies, bone marrow failure, and childhood cancer predisposition, highlighting the gene’s essential role in DNA repair. From a molecular standpoint, PALB2 encodes a critical partner of BRCA1 and BRCA2 within the homologous recombination (HR) DNA repair pathway. Loss of function variants result in homologous recombination deficiency (HRD), which has therapeutic relevance, as tumors harboring germline or somatic PALB2 pathogenic variants may demonstrate sensitivity to PARP inhibitors and platinum based chemotherapy. Identification of a pathogenic PALB2 variant has important clinical management implications, including enhanced breast cancer surveillance (e.g., annual breast MRI), consideration of risk reducing strategies, and cascade testing for at risk relatives, in accordance with established professional guidelines.

Links

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

References

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1. 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.
2. 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.
3. 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.
4. 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.
5. Slavin TP, et al. The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer. 2017;3:22.
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16. Quigley D, et al. Analysis of circulating tumor DNA identifies reversion mutations associated with therapeutic resistance. Sci Transl Med. 2017.
17. Edwards SL, et al. Resistance to therapy caused by intragenic deletion in BRCA2; analogous mechanisms in PALB2-deficient tumors. Nature. 2008.
18. Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497–506.
19. lavin TP, et al. The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer. 2017;3:22.
20. National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2024.
21. Southey MC, et al. PALB2 splice variants and breast cancer risk. Breast Cancer Res. 2016;18:14.
22. Richards S, et al. Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405–424.
23. Park JY, et al. Efficacy of PARP inhibitors in PALB2-mutated cancers. Clin Cancer Res. 2021;27(15):4231–4240.
24. Mateo J, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2019;373(18):1697–1708.

Notes

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