GTS5:PALB2-related cancer predisposition syndrome (PALB2) - Revision history

Kgeiersbach: Accepted changes, made a few minor edits including a few references added. Added a gene diagram.

2026-01-17T00:11:15Z

Accepted changes, made a few minor edits including a few references added. Added a gene diagram.

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Parisa.Kargaran at 20:29, 16 January 2026

2026-01-16T20:29:40Z

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Parisa.Kargaran at 14:20, 16 January 2026

2026-01-16T14:20:57Z

← Older revision		Revision as of 09:20, 16 January 2026
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	<span style="color:#0070C0">(''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 [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)\|<u>FAQs</u>]] as well as contact your [[Leadership\|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>		<span style="color:#0070C0">(''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 [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)\|<u>FAQs</u>]] as well as contact your [[Leadership\|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>
	==Primary Author(s)*==		==Primary Author(s)*==
			Parisa Kargaran, Ph.D.

	Hieu Nguyen, Ph.D., FACMG		Hieu Nguyen, Ph.D., FACMG

	~~Parisa Kargaran, Ph.D.~~
	==WHO Classification of Disease==		==WHO Classification of Disease==

Parisa.Kargaran at 14:18, 16 January 2026

2026-01-16T14:18:44Z

Show changes

Parisa.Kargaran at 12:44, 16 January 2026

2026-01-16T12:44:38Z

← Older revision		Revision as of 07:44, 16 January 2026
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	==== Biallelic State (Compound Heterozygous or Homozygous Pathogenic Variants) ====		==== 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<ref name=":13" /><ref name=":15" /><ref>Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010;70(19):7353–7359</ref>.		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>.

	==== Incidence ====		==== Incidence ====
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	(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''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''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span>		(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''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''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span>

	<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=":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.
	<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.		# <ref name=":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.
			# <ref name=":5" />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.
	<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 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 name=":15" />Tischkowitz M, et al. Management of PALB2-associated breast cancer risk. Lancet Oncol. 2017;18(2):e75–e86.
	<ref name=":2" />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.		# <ref name=":13" />Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype N. Nat Genet. 2007.
			# <ref name=":23" />Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010;70(19):7353–7359
	~~<ref name=":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.~~		# <ref name=":8" />National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Current version.
			# <ref name=":2" />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.
	<ref name=":4" />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.		# <ref name=":4" />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.
			# <ref name=":6" />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.
	<ref name=":5" />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.		# <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 name=":9" />International Agency for Research on Cancer (IARC). WHO Classification of Tumours. Genetic tumour syndromes and DNA repair–related cancer susceptibility.
	<ref name=":6" />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.		# <ref name=":10" />Goodall J, et al. Circulating tumor DNA to identify reversion mutations associated with acquired resistance to PARP inhibitors. J Clin Oncol. 2017.
			# <ref name=":11" />Quigley D, et al. Analysis of circulating tumor DNA identifies reversion mutations associated with therapeutic resistance. Sci Transl Med. 2017.
	<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 name=":12" />Edwards SL, et al. Resistance to therapy caused by intragenic deletion in BRCA2; analogous mechanisms in PALB2-deficient tumors. Nature. 2008.
			# <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 name=":8" />National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Current version.~~		# <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 name=":17" />National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2024.
	<ref name=":9" />International Agency for Research on Cancer (IARC). WHO Classification of Tumours. Genetic tumour syndromes and DNA repair–related cancer susceptibility.		# <ref name=":18" />Southey MC, et al. PALB2 splice variants and breast cancer risk. Breast Cancer Res. 2016;18:14.
			# <ref name=":19" />Richards S, et al. Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405–424.
	<ref name=":10" />Goodall J, et al. Circulating tumor DNA to identify reversion mutations associated with acquired resistance to PARP inhibitors. J Clin Oncol. 2017.		# <ref name=":20" />Park JY, et al. Efficacy of PARP inhibitors in PALB2-mutated cancers. Clin Cancer Res. 2021;27(15):4231–4240.
			# <ref name=":21" />Mateo J, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2019;373(18):1697–1708.
	<ref name=":11" />Quigley D, et al. Analysis of circulating tumor DNA identifies reversion mutations associated with therapeutic resistance. Sci Transl Med. 2017.

	<ref name=":12" />Edwards SL, et al. Resistance to therapy caused by intragenic deletion in BRCA2; analogous mechanisms in PALB2-deficient tumors. Nature. 2008.

	~~<ref name=":13" />Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype N. Nat Genet. 2007.~~

	<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 name=":15" />Tischkowitz M, et al. Management of PALB2-associated breast cancer risk. Lancet Oncol. 2017;18(2):e75–e86.~~

	<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 name=":17" />National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2024.

	<ref name=":18" />Southey MC, et al. PALB2 splice variants and breast cancer risk. Breast Cancer Res. 2016;18:14.

	<ref name=":19" />Richards S, et al. Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405–424.

	<ref name=":20" />Park JY, et al. Efficacy of PARP inhibitors in PALB2-mutated cancers. Clin Cancer Res. 2021;27(15):4231–4240.

	<ref name=":21" />Mateo J, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2019;373(18):1697–1708.

	==Notes==		==Notes==

Parisa.Kargaran at 12:31, 16 January 2026

2026-01-16T12:31:37Z

Parisa.Kargaran at 12:27, 16 January 2026

2026-01-16T12:27:09Z

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 ====== Cancer risk estimates for heterozygous carriers: ======
-Relative risk: ~5-fold compared with the general population
+* 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" />
+* Relative risk: ~5-fold compared with the general population
 === PALB2 Related Cancer Predisposition Syndrome: ===

Parisa.Kargaran at 12:18, 16 January 2026

2026-01-16T12:18:54Z

← Older revision		Revision as of 07:18, 16 January 2026
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	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" />		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" />

			=== 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<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>.

			====== 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<ref name=":3" /><ref name=":15" />

	=== PALB2 Related Cancer Predisposition Syndrome: ===		=== PALB2 Related Cancer Predisposition Syndrome: ===
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	<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.		<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.

			<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 name=":2" />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.		<ref name=":2" />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.

Parisa.Kargaran at 12:03, 16 January 2026

2026-01-16T12:03:13Z

← Older revision		Revision as of 07:03, 16 January 2026
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	Put your text here <span style="color:#0070C0">(''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.'')</span>		Put your text here <span style="color:#0070C0">(''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.'')</span>

	- 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.		== PALB2 – Gene Function and Clinical Relevance ==

	~~- 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.~~		=== 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<ref name=":0" /><ref name=":1" />

	- 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 Related Cancer Predisposition Syndrome: ===

Parisa.Kargaran at 01:59, 16 January 2026

2026-01-16T01:59:25Z

← Older revision		Revision as of 20:59, 15 January 2026
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	\|''PALB2''; Biallelic germline variants		\|''PALB2''; Biallelic germline variants
	\|Fanconi anemia (FA) pathway / interstrand crosslink repair		\|Fanconi anemia (FA) pathway / interstrand crosslink repair
	\|~~ailure~~ of FA pathway coordination causes Fanconi anemia complementation group N, characterized by bone marrow failure, developmental abnormalities, and early-onset malignancies<ref name=":2" /><ref name=":13">Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype N. Nat Genet. 2007.</ref>		\|Failure of FA pathway coordination causes Fanconi anemia complementation group N, characterized by bone marrow failure, developmental abnormalities, and early-onset malignancies<ref name=":2" /><ref name=":13">Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype N. Nat Genet. 2007.</ref>
	\|-		\|-
	\|''PALB2''; Reversion mutations (therapy-associated)		\|''PALB2''; Reversion mutations (therapy-associated)
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	Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>		Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>

	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" />.		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" />.

	==Additional Information==		==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<ref name=":14" /><ref name=":15" />. 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<ref name=":5" /><ref name=":17" />. 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<ref name=":13" />. 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<ref name=":20">Park JY, et al. Efficacy of PARP inhibitors in PALB2-mutated cancers. Clin Cancer Res. 2021;27(15):4231–4240.</ref><ref name=":21">Mateo J, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2019;373(18):1697–1708.</ref>. 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<ref name=":17" />.		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<ref name=":14" /><ref name=":15" />. 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<ref name=":5" /><ref name=":17" />. 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<ref name=":13" />. 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<ref name=":20">Park JY, et al. Efficacy of PARP inhibitors in PALB2-mutated cancers. Clin Cancer Res. 2021;27(15):4231–4240.</ref><ref name=":21">Mateo J, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2019;373(18):1697–1708.</ref>. 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<ref name=":17" />.

	==Links==		==Links==

← Older revision		Revision as of 07:31, 16 January 2026
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	=== Clinical Phenotypes by Zygosity ===		=== Clinical Phenotypes by Zygosity ===

	===== Heterozygous State (Monoallelic Pathogenic Variants) =====		==== 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<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>.		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>.

	====== Cancer risk estimates for heterozygous carriers: ======		==== Cancer risk estimates for heterozygous carriers: ====

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

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

	====== Biallelic State (Compound Heterozygous or Homozygous Pathogenic Variants) ======		==== 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<ref name=":13" /><ref name=":15" /><ref>Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010;70(19):7353–7359</ref>.		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>Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010;70(19):7353–7359</ref>.

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

	====== Summary of Cancer Risks in Heterozygous Carriers ======		==== Summary of Cancer Risks in Heterozygous Carriers ====
	Heterozygous pathogenic variants in PALB2 are associated with:		Heterozygous pathogenic variants in PALB2 are associated with:

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	=== PALB2 Related Cancer Predisposition Syndrome: ===		=== 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 <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> <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.</ref><ref name=":2">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.</ref>. 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 <ref name=":0" /><ref name=":1" /><ref name=":2" />.		''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 <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><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.</ref><ref name=":2">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.</ref>. 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 <ref name=":0" /><ref name=":1" /><ref name=":2" />.

	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<ref name=":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.</ref><ref name=":4">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.</ref><ref name=":5">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.</ref>. In some families, breast cancer risks approach those observed in BRCA2 carriers<ref name=":3" /><ref name=":5" />. 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<ref name=":4" /><ref name=":6">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.</ref>. An increased risk of male breast cancer has also been reported relative to the general population <ref name=":5" />.		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<ref name=":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.</ref><ref name=":4">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.</ref><ref name=":5">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.</ref>. In some families, breast cancer risks approach those observed in BRCA2 carriers<ref name=":3" /><ref name=":5" />. 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<ref name=":4" /><ref name=":6">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.</ref>. An increased risk of male breast cancer has also been reported relative to the general population <ref name=":5" />.