• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The PALB2 gene is associated with an increased risk for autosomal dominant breast and pancreatic cancer, and possibly ovarian cancer, in individuals who carry a single pathogenic PALB2 variant (PMID: 25099575, 17200668, 18628482). Additionally, the PALB2 gene is associated with autosomal recessive Fanconi anemia (MedGen UID: 372133).

PALB2 is a tumor suppressor gene encoding the partner and localizer of BRCA2 protein, which plays a role in DNA damage repair, cell growth and division. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) and permits the stable intranuclear localization and accumulation of BRCA2. Loss of PALB2 function due to mutations causes defective DNA repair, leading to accumulation of DNA damage, thereby increasing the risk of tumor formation.

PALB2 heterozygote
OMIM: 610355

Clinical condition
The risk of breast cancer in women with a single pathogenic PALB2 variant is 33-58% by age 70, with higher risks among those with a greater number of relatives with breast cancer (PMID: 25099575, 17200668, 18628482, 21285249). One study found the risk of developing contralateral breast cancer is approximately 10% within five years after the initial diagnosis of breast cancer among individuals with a pathogenic variant in PALB2 (PMID: 25959805).

For both men and women, there is also an increased risk for pancreatic cancer, however, specific risk figures are not yet established (PMID: 20412113, 19264984, 21285249). Additional data suggests an increased risk of ovarian cancer (PMID: 26075229, 22505525) and male breast cancer (PMID: 28008555, 27648926, 21285249), although this evidence is limited and emerging.

Gene information
PALB2 is a tumor-suppressor gene, meaning its function is to help control the rate of growth and cell division in the body. The protein product plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks (Uniprot: PALB2_HUMAN,Q86YC2 http://www.uniprot.org/uniprot/Q86YC2. Accessed January 2017). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers may be increased.

Hereditary predisposition to cancer due to pathogenic variants in the PALB2 gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases may occur spontaneously (i.e., an individual with a pathogenic variant who has parents who do not have it).

Individuals with a single pathogenic PALB2 variant are also carriers of autosomal recessive Fanconi anemia type N. Fanconi anemia is characterized by bone marrow failure with variable additional anomalies, which often include short stature, abnormal skin pigmentation, abnormal thumbs, malformations of the skeletal and central nervous systems, and developmental delay (PMID: 8986277, 20417588). Risk of leukemia and early onset solid tumors is significantly elevated with this disorder (PMID: 12393424, 12393516, 20507306). For there to be a risk of Fanconi anemia in offspring, both the patient and their partner would each have to carry a pathogenic variant in PALB2; in this case, the risk to have an affected child is 25%.

The National Comprehensive Cancer Network® (NCCN®) has published screening and surveillance guidelines for women with a single pathogenic variant in PALB2 (NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2018):

  • Annual mammography with consideration of tomosynthesis beginning at age 30
  • Consider annual breast MRI with contrast starting at age 30, with modification as appropriate based on family history
  • Prophylactic risk-reducing mastectomy: consider based on family history (evidence insufficient; manage based on family history)
  • Referral to genetic counseling for a discussion regarding recurrence risks for both autosomal dominant and autosomal recessive PALB2-related conditions

NCCN cites insufficient evidence to warrant screening for ovarian and pancreatic cancer (NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2018). In contrast, the American College of Gastroenterology Clinical Guidelines recommend pancreatic cancer screening in PALB2 carriers be limited to those with a first- or second-degree relative affected with pancreatic cancer. Ideally, screening should be performed in experienced centers utilizing a multidisciplinary approach under research conditions. Recommended screening includes annual endoscopic ultrasound and/or MRI of the pancreas starting at age 50 or 10 years younger than the earliest age of pancreatic cancer diagnosis in the family (PMID: 25645574).

Overall cancer risk assessment incorporates additional factors including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a PALB2 pathogenic variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding PALB2 are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow recommended screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Additional reference
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial High-Risk Assessment: Breast and Ovarian V.1.2018. ©National Comprehensive Cancer Network, Inc 2017. All rights reserved. Accessed October 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. National Comprehensive Cancer Network®, NCCN®, NCCN Guidelines®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Review date: October 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
PALB2 NM_024675.3