GTS5:PALB2-related cancer predisposition syndrome (PALB2)

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

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

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

Put your text here (Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.)

- 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

Put your text here and fill in the table (Instructions: Describe germline alteration(s) that cause the syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetics-related information. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. Please include references throughout the table. Do not delete the table.)

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

Put your text here and fill in the table (Instructions: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information. Please include references throughout the table. Do not delete the table.)

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

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

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

Put your text here (Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.)

Additional Information

Put your text here

Links

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

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)

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.

Goodall J, et al. Circulating tumor DNA to identify reversion mutations associated with acquired resistance to PARP inhibitors. J Clin Oncol. 2017.

Quigley D, et al. Analysis of circulating tumor DNA identifies reversion mutations associated with therapeutic resistance. Sci Transl Med. 2017.

Edwards SL, et al. Resistance to therapy caused by intragenic deletion in BRCA2; analogous mechanisms in PALB2-deficient tumors. Nature. 2008.

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):