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

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).

PALB2-Related Cancer Predisposition Syndrome:

PALB2 related cancer predisposition syndrome is an autosomal dominant hereditary cancer susceptibility syndrome caused by heterozygous pathogenic or likely pathogenic germline variants in PALB2 (Partner of BRCA2), a tumor suppressor gene that encodes a critical mediator of homologous recombination mediated DNA double strand break repair through its interaction with BRCA2. The syndrome is primarily associated with a substantially increased lifetime risk of breast cancer, with cumulative risk estimates approaching those observed in BRCA2 carriers in some families

Epidemiology/Prevalence

- 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.

Genetic Abnormalities: Germline

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Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
PALB2	SNVs (frameshift, nonsense, missense, splice site, synonymous splice mutations); CNVs (inactivating deletions or duplications)	Multiple variant types leading to loss of function	Autosomal dominant, ~35-60% penetrance for carriers. Autosomal recessive, Fanconi anemia (FA) subtype N, 100% penetrance.

Genetic Abnormalities: Somatic

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Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
EXAMPLE: BRCA1	EXAMPLE: Biallelic inactivation variants	EXAMPLE: Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.
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, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22:719–729.

Sy SMH, Huen MSY, Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci USA. 2009;106:7155–7160.

Notes

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Prior Author(s):