GTS5:PALB2-related cancer predisposition syndrome (PALB2): Difference between revisions

==Definition/Description of Disease==

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<ref name=":0" /><ref name=":1" />

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<ref name=":3" /><ref name=":5" />. 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<ref name=":22">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.</ref>.

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

* Tumor phenotype: Enrichment of triple-negative breast cancer among ''PALB2''-associated breast cancers<ref name=":3" /><ref name=":15" />

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<ref name=":13" /><ref name=":15" /><ref name=":23">Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010;70(19):7353–7359</ref>.

The estimated population frequency of pathogenic ''PALB2'' variants is approximately 0.1% <ref name=":15" /><ref name=":5" />.

Heterozygous pathogenic variants in ''PALB2'' are associated with:

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 <ref name=":7">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.</ref><ref name=":8">National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Current version.</ref>. Associations with ovarian cancer have been described, although penetrance appears lower than that observed for ''BRCA1'' and ''BRCA2'' <ref name=":3" /><ref name=":5" />.

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<ref name=":4" /><ref name=":5" />. 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<ref name=":4" /><ref name=":7" />. Once a pathogenic variant is identified, cascade testing of at-risk relatives is recommended<ref name=":5" /><ref name=":8" />.

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<ref name=":3" /><ref name=":4" /><ref name=":5" />. Distinction among these conditions relies on germline genetic testing, tumor characteristics, and family history patterns.

==Genetic Abnormalities: Germline==

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==Genetic Abnormalities: Somatic==

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==Genes and Main Pathways Involved==

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==Genetic Diagnostic Testing Methods==

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<ref name=":14">Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497–506.</ref><ref name=":15">Tischkowitz M, et al. Management of PALB2-associated breast cancer risk. Lancet Oncol. 2017;18(2):e75–e86</ref>. 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<ref name=":16">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.</ref><ref name=":17">National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2024</ref>. 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 <ref name=":18">Southey MC, et al. PALB2 splice variants and breast cancer risk. Breast Cancer Res. 2016;18:14.</ref>. 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<ref name=":19">Richards S, et al. Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405–424</ref><ref name=":17" />.

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

==References==

# <ref name=":0" />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.

# <ref name=":1" />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.