PALB2

PALB2-Related Cancer Risk

The PALB2 gene plays an important role in allowing the cell to repair itself and is a partner of BRCA2.

The PALB2 gene is classified as a “moderate risk” gene, meaning that there is a modestly increased risk for certain types of cancers.  For example, women who have one PALB2 pathogenic gene mutation likely have a relative risk of approximately 3 for breast cancer in comparison to the general population.

PALB2 gene mutations have also been linked to an increased risk for pancreatic and prostate cancer, but the lifetime risks for these types of cancer are not yet defined.  Further research is needed to understand the interactions of moderate risk genes and family history on lifetime cancer risk.

Rarely, an individual will inherit two PALB2 gene mutations – one from each parent.  When this happens, the child has a severe disease called Fanconi Anemia.  Children who have AT have blood problems, developmental issues, and increased risk of cancers such as leukemia and lymphoma.

PALB2 cancer screening and risk-reducing options

There is currently no agreement within the medical community on the best long-term medical management for an individual who carries a mutation in the PALB2 gene.  Healthcare providers oftentimes rely on an individual’s personal and family history to guide medical care.   The NCCN and the PROMPT study team currently recommend for mutations carriers mammogram start at the age of 30 and MRI with contrast and risk reductive-mastectomy are considered options. There is currently insufficient evidence to recommend risk reductive salpingo-oophorectomy on the basis of a PALB2 mutation alone.

Depending upon personal and family history, some women may consider increased breast cancer surveillance such as mammogram and breast MRI.

At this time, there is no proven form of screening for pancreatic cancer. Some hospitals may offer research-based screening with imaging exams (MRI, CT, and endoscopic ultrasound) and blood work.  Potential benefits, risks and limitations of research-based screening should be understood.

Depending upon personal and family history, some men may consider increased prostate cancer surveillance such as PSA blood testing and digital rectal examination.

As research continues to evolve, physicians and researchers will gain a better understanding of how an PALB2 gene mutation will guide medical care.  Because the information provided to patients will almost certainly change, those with an PALB2 gene mutation are encouraged to keep in touch with their medical providers in order to receive updates.

PALB2 testing in other family members

At this point in time, testing adult family members for a moderate risk gene mutation does NOT provide the same clarity or guidance that testing for a high risk gene mutation does. This is because moderate risk gene mutations should not be assumed to be the sole explanation for a particular family’s history of cancer.  For example, a family could have additional undetected/ unknown genetic and/or non-genetic risk factors contributing to the development of cancer seen in family members.  It is recommended that concerned family members discuss the issue of testing with their physicians and screening options.  However, given the current lack of data regarding PALB2 gene mutations, if an adult family member were to test negative for a familial PALB2 gene mutation, that individual may still be at increased risk for cancer depending upon the family history and possibility for other genes to be playing a role in that individual/ family.

Because of the potential risk for children to be affected with Fanconi anemia if both of their parents have PALB2 gene mutations, family members who are considering having children should speak with a genetic counselor to discuss risks and the possibility of having their partner tested before conceiving.

Significance of pathogenic or likely pathogenic change in PALB2

When pathogenic (harmful) or likely pathogenic (likely harmful) changes (mutations) are detected in PALB2, this information is informative in 4 ways:

  1. Diagnostics: It might have contributed to a cancer developing and provides part of an explanation as to why someone develops cancer.
  2. Prevention: If identified in other family members, early screening or risk reductive surgical planning should be reviewed with an individual’s medical team. Evidenced based counseling framework related literature.
  3. Therapeutics: The PALB2 gene produces a protein in the body essential for repair of cells and if this function is altered, a cell may be unstable and develop into a cancer. Specific medications are being studied as part of clinical trials for people with an inability to appropriately repair their DNA due to changes in PALB2 and other DNA damage related genes. Clinical Trials
  4. Family Planning: Some individuals and families may decide to use genetic information for planning a family.  It is important to know for PALB2 mutations carriers in addition to a 50% risk for an offspring to also inherit a damaging change, in the exceedingly rare circumstance  both parents carry a harmful change (mutation) in the same gene a rare and severe disease may occur in infancy or childhood with a probability of 25% for each pregnancy.

Variant of Uncertain Significance (VUSs) in the PALB2 gene

In order for a change in a gene to be determined as pathogenic or likely pathogenic significant evidence or burden of proof is needed given the importance of decisions and recommendations to be made, therefore variants of uncertain significance which have not met this burden of proof should not guide recommendations.

Data Repositories for PALB2 Variants

The federal government is invested in learning more about variants of uncertain significance and tracking these variants in a central source called ClinVar.  However, significant expertise and curation is required before variants are deposited in this central source. PROMPT is dedicated to generating quality data.

The consequences of misclassification can be significant and costly when individuals make life impacting decisions.  Recently, the PROMPT study team illustrated in work spearheaded by Balamana et al. how different variants may be classified and the potential consequences of mis-classification based on the 4 main uses of this information by individuals and providers.

Resources/ References

More information on the PALB2 gene:

  1. Gene Information:   OMIM: 610355, Orphanet, DECIPHER
  2. Where to send testing:  GeneTests
  3. Catalogue of mutations:  LSDB:Fanconi anemia database, ,
  4. Registry information: Genetic Testing Registry

References:

  1. Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13(9):581-8. doi: 10.1038/nrclinonc.2016.90. PubMed PMID: 27296296.
  2. Pritchard CC, Mateo J, Walsh MF, et al: Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375:443-53, 2016
  3. Salo-Mullen EE, O’Reilly EM, Kelsen DP, et al: Identification of germline genetic mutations in patients with pancreatic cancer. Cancer 121:4382-8, 2015
  4. Grant RC, Selander I, Connor AA, et al: Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology 148:556-64, 2015
  5. Thompson ER, Rowley SM, Li N, et al. Panel testing for familial breast cancer: calibrating the tension between research and clinical care. J Clin Oncol 2016;34:1455–1459.
  6.  Casadei S, Norquist BM, Walsh T, et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res 2011;71:2222–2229.
  7.  Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 2015;33:304–311.
  8. Cybulski C, Kluzniak W, Huzarski T, et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol 2015;16:638–644.
  9.  Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014;371:497–506.
  10. Kanchi KL, Johnson KJ, Lu C, et al. Integrated analysis of germline and somatic variants in ovarian cancer. Nat Commun 2014;5:3156.
  11.  Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res 2010;70:7353–7359