INTRODUCTION — This monograph summarizes the interpretation of germline testing of the PALB2 gene. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. These subjects are discussed separately [1].
OVERVIEW
How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).
Testing involves two steps by the laboratory: determining the genotype and interpreting the pathogenicity of the variant(s).
The pathogenicity of each variant is classified by the laboratory into one of five categories (table 2), using information available at the time [2].
Classification of variants — The classification for many variants such as those deemed "likely pathogenic" or "variants of uncertain significance" (VUS) is periodically updated as more data become available [3]. The uncertainty reflects the available research rather than the accuracy of genotyping.
If there is concern about the classification, such as for a VUS or low-penetrance variant, obtain an updated interpretation periodically (eg, annually), when clinical management or reproductive decisions might be altered or if family members present for genetic testing. This can be done by checking a database such as ClinVar, contacting the laboratory, or consulting a specialist, clinical geneticist or genetic counselor (see 'Locating a genetics expert' below); there is no gold standard approach. Some laboratories routinely provide updates and others provide more information only when requested. Many VUS are reclassified as benign. Likely benign and benign variants are not routinely reported.
●Genotype – Identifies the variants in the gene(s) tested. If the results were obtained by direct-to-consumer testing or a research study, testing should be repeated, possibly in conjunction with additional gene tests, in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other nationally certified laboratory). This is particularly true if test results would impact clinical care of the patient and/or their relatives (eg, pathogenic variant identified in a gene with known clinical significance/potential clinical actionability; negative finding in an individual with a suspected cancer syndrome or whose at-risk relative is known to carry a pathogenic variant).
●Interpretation – Determines pathogenicity of the variant(s) identified and presents a classification of such based on standard criteria. May require updating, particularly for VUS, as new research and data are available. (See 'Variant of uncertain significance' below.)
The table provides a glossary of genetic testing terms (table 3).
Disease associations — Partner and localizer of BRCA2 (PALB2) is a cancer susceptibility gene that encodes a BRCA2-interacting protein [4]. The BRCA2-PALB2 interaction is crucial for key BRCA2 DNA damage response functions as well as tumor suppressor activity.
PALB2 is considered a moderate to high-risk cancer gene. Inheritance is autosomal dominant with incomplete penetrance. Heterozygosity for a pathogenic or likely pathogenic variant in PALB2 is associated with increased lifetime risk for several cancers, but many individuals will not develop cancer [5]:
●Breast cancer (female) – Absolute risk 41 to 60 percent
●Pancreatic cancer (exocrine) – Absolute risk 5 to 10 percent
●Ovarian cancer – Absolute risk 3 to 5 percent
While the risks for breast and pancreatic cancer are relatively well established, risks for the other types of cancers (and breast cancer in males) are not confirmed and/or are difficult to quantify. Other genetic and environmental factors may contribute to overall risk. (See "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2", section on 'PALB2' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Hereditary breast cancer: BRCA and PALB2'.)
Although rare, biallelic pathogenic variants in PALB2 (one pathogenic variant inherited from each parent) are associated with Fanconi anemia. This is an autosomal recessive condition. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Genetics'.)
INDIVIDUALS WITHOUT CANCER
Pathogenic or likely pathogenic variant — We treat all variants in PALB2 that are pathogenic or likely pathogenic the same for purposes of counseling and cancer risk management, regardless of the initial reason for testing. The risk of breast and ovarian cancer in PALB2 carriers appears to be higher in females who have first-degree relatives affected with these cancers. Therefore, risk estimation should consider the family history. In the future, polygenic risk scores are likely to be used to further individualize cancer risks [6].
Discussion should include the range of cancer risks, possible interventions for surveillance or risk reduction, and implications for first-degree and more distant relatives (see 'At-risk relatives' below). The discussion of risks is individualized based on the person's age and, possibly, family history of cancer.
Counseling may require additional visits or referral to a genetic counselor, clinical geneticist, or oncologist. Acting upon genetic test results is usually not an emergency; the individual can be reassured that management decisions can be deferred until questions have been answered.
We adhere to the National Comprehensive Cancer Network (NCCN) recommendations for surveillance and risk reduction [5]. The type of cancer and age of onset in a family member may also inform risk assessment and screening (eg, screening at an earlier age if a family member has an earlier age of onset).
Several evaluations and interventions can reduce the risk of PALB2-associated cancers. Use of these strategies depends on the patient's age, values, and preferences (algorithm 1).
Interventions for cancer screening or risk reduction
Female breast cancer
●Increased surveillance:
•Annual breast magnetic resonance imaging (MRI) with contrast starting at age 30 years.
•Annual mammography with consideration of tomosynthesis starting at age 30 years.
•Individualized management after age 75 years.
●Discussion of risk-reducing bilateral mastectomy, with shared decision-making [7].
●There are no data about efficacy of hormonal chemoprevention (tamoxifen or aromatase inhibitor); moreover, studies have found that there is an increased risk of triple-negative breast cancer in PALB2 carriers. Therefore, the benefits of this approach are unknown in PALB2 carriers.
Ovarian cancer
●Discussion of risk-reducing bilateral salpingo-oophorectomy (rrBSO) for individuals with a family history of ovarian cancer, particularly in first-degree relatives. Such surgery can occur after menopause, unless there is a family history of premenopausal ovarian cancer. (See "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2", section on 'PALB2'.)
Pancreatic cancer
●Discussion of screening for those with a family history of pancreatic cancer in a first- or second-degree relative that appears to be on the same side of the family as the pathogenic variant. Usually, this is done by contrast-enhanced MRI/magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound (EUS). (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Screening modality and timing'.)
Negative test — Negative testing means no pathogenic variants were identified (algorithm 1).
●If a familial PALB2 pathogenic variant is identified and the tested individual does not have that variant, usually they can be reassured that they are unlikely to be at high risk for PALB2-associated cancers, with the caveats outlined above (see 'How to read the report' above). However, it is important to assess family history, including family history on the side of the family without the PALB2 pathogenic variant, as well as other personal cancer risk factors to provide an individualized risk assessment. As with variants in other genes in which the risk assessment is particularly dependent on family history, relatives who test negative for the familial pathogenic variant may not have cancer risks that are reduced to the level of the general population [8,9]. Thus, unlike at-risk individuals in BRCA1/2-positive kindreds who receive a "true negative" result and can usually be reassured that their breast and ovarian cancer risks are about the same as the general population [10,11], such reassurance may not always be possible when there is a PALB2 pathogenic variant in the family.
●If a familial variant in PALB2 is not known and results of genetic testing are negative, additional risk factors for cancer (genetic or acquired) may be present, and comprehensive testing with a cancer gene panel may be recommended. Surveillance and risk reduction recommendations are based on personal risk factors and family history. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to determine optimal testing in those with a strong or suggestive family history of cancer. (See 'Locating a genetics expert' below.)
Variant of uncertain significance — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history and not the VUS (algorithm 1).
New information may become available, and the testing laboratory or other resource should be consulted periodically for updates in the classification (eg, annually). (See 'Classification of variants' above.)
INDIVIDUALS WITH CANCER — The implications of genetic test results should be discussed with the individual's oncologist or surgeon; in some cases, referral to a specialist in cancer genetics may be appropriate.
In general, the choice of chemotherapy is not affected by PALB2 status, although some studies suggest that DNA-damaging agents, such as platinum-based chemotherapy, may be particularly effective in PALB2 carriers. Additionally, individuals with germline PALB2 pathogenic variants may be candidates for treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. (See "Overview of the approach to metastatic breast cancer", section on 'Special considerations'.)
A pathogenic or likely pathogenic variant in PALB2 may impact cancer surgery, surveillance, and risk reduction:
●It may prompt a female patient to seek bilateral mastectomy to reduce the risk of second primary breast cancer. However, the risk of contralateral breast cancer is not well established.
●Additional surveillance and risk-reducing measures may be warranted, particularly for ovarian cancer. (See 'Pathogenic or likely pathogenic variant' above.)
Genetic counseling and testing of adult first- and second-degree relatives are also appropriate. (See 'Considerations for the family' below.)
Further discussion of cancer risks associated with PALB2-pathogenic variants is presented separately. (See "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2", section on 'PALB2'.)
For individuals with negative genetic testing or a variant of uncertain significance (VUS) for whom there are reasons to be concerned about a hereditary cause, additional genetic testing may be appropriate based on personal and family history of cancer. The need for additional testing may be discussed with a genetic counselor, clinical geneticist, or the primary oncologist, or other specialists with expertise in managing hereditary cancer syndromes. (See 'Locating a genetics expert' below.)
CONSIDERATIONS FOR THE FAMILY
Reproductive counseling — Reproductive counseling (ideally done prior to conception) is appropriate for individuals with a pathogenic or likely pathogenic variant in PALB2 who are considering childbearing or may wish to have children in the future.
Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT) or prenatal diagnosis. (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)
At-risk relatives — Individuals who test positive for a pathogenic or likely pathogenic variant should inform their relatives about the importance of genetic counseling and the option of genetic testing.
●The risk of having inherited or having the variant is 50 percent for first-degree relatives (parents, male and female siblings, children). Other at-risk relatives may include aunts, uncles, nieces, nephews, and cousins.
●Because it is very rare for PALB2-associated cancers to occur before adulthood, genetic testing is generally deferred until ≥18 years to allow for informed consent. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)
RESOURCES
UpToDate topics
●PALB2 associated cancers:
•Cancer risks – (See "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2", section on 'PALB2'.)
•Genetic testing – (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)
•Breast cancer – (See "Factors that modify breast cancer risk in women" and "ER/PR negative, HER2-negative (triple-negative) breast cancer" and "Contralateral prophylactic mastectomy" and "Breast cancer in men" and "Overview of the approach to metastatic breast cancer".)
•Pancreatic cancer – (See "Familial risk factors for pancreatic cancer and screening of high-risk patients".)
●Genetics:
•Variant classification – (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)
•Terminology – (See "Genetics: Glossary of terms".)
Locating a genetics expert
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC)
