PALB2 is a tumour suppressor gene with a role in the homologous recombination repair (HRR) pathway, through interaction with both BRCA1 and BRCA2. HRR is the major pathway for the repair of double-stranded DNA breaks. This is clinically important as failure of this pathway means that precision treatment options may be available for patients affected with HRR-deficient cancers (for example, PARP inhibitors).
Gene locus and structure
- Located at chromosome 16q12.2.
- Contains 13 exons.
- The PALB2 protein includes a number of domains, including an amino terminal coiled-coil domain at the N terminus, at which interaction with BRCA1 occurs, and at the C terminus – a WD40 repeat domain, at which BRCA2 binding occurs. PALB2 also includes a central chromatin-associated motif.
- The population frequency of likely pathogenic/pathogenic variants is estimated to be in the order of 1/770; rarer than those in BRCA1 (1 in 381) or BRCA2 (1 in 277).
- Routine diagnostic constitutional (germline) genetic testing of PALB2 in patients with cancer has been introduced more recently than testing of BRCA1/BRCA2, such that data are still being gathered on mutational spectrum and genotype/phenotype correlations (if any).
- Over 900 pathogenic/likely pathogenic variants in PALB2 have been described to date, the overwhelming majority of which are truncating variants (nonsense or frameshift), although pathogenic/likely pathogenic missense variants or large genomic rearrangements have rarely been described.
- A number of recurrent variants have been described, which account for more than half of likely pathogenic/pathogenic variants reported to date:
- PALB2: c.509_510delGA (p.Arg170IlefsTer14)
- PALB2: c.3113G>A (p.Trp1038Ter)
- PALB2: c.1592delT (p.Leu531Cysfs*30)
- PALB2: 172_175delTTGT (p.Gln60Argfs*7)
- PALB2: c.1240C>T (p.Arg414Ter)
Hereditary cancer risk
Constitutional (germline) pathogenic variants in PALB2 are associated with a high risk of breast cancer and a moderately increased risk of ovarian, pancreatic and possibly other cancers.
Estimated lifetime cancer risks for carriers of pathogenic constitutional (germline) variants in PALB2 include:
|Cancer||Population risk (%)||PALB2 variant carrier (%)|
|Female breast cancer*||12||44-63%|
|Male breast cancer*||0.1||~0.2-5%|
*Note: Risks in transwomen are uncertain, but are likely to be lower than those in women but higher than those in men.
**including tubal and primary peritoneal cancers
- There is some evidence to suggest enrichment of the triple-negative subtype of breast cancer in carriers of PALB2 variants compared to the general population, but the majority of PALB2-associated breast tumours are ER-positive.
- The risk of second primary breast cancers in carriers of likely pathogenic/pathogenic variants in PALB2 is uncertain, but there is some evidence to suggest it is increased.
- Ovarian cancer occurring in carriers of pathogenic PALB2 variants is typically of the high-grade serous subtype. The vast majority of cases of ovarian cancer occur after the age of 50 in carriers of pathogenic PALB2 variants, with an estimated risk of <1%. before that age.
- Tumours occurring in carriers of pathogenic variants in PALB2 may demonstrate homologous recombination repair deficiency (HRD). Sporadic cancers occurring by chance (for example, lung or skin cancers) in carriers of such variants may not demonstrate these features.
Recessive disorders associated with pathogenic variants in PALB2
Individuals that carry pathogenic variants in both copies of their PALB2 gene (biallelic variants) are affected by a condition known as Fanconi anaemia, a chromosomal fragility syndrome characterised by congenital abnormalities of the skeleton, eye or genitourinary system, short stature, progressive bone marrow failure and predisposition to haematological and solid tumours.
The clinical phenotype associated with pathogenic/likely pathogenic variants in PALB2 may be clinically indistinguishable from that associated with likely pathogenic/pathogenic variants in BRCA1, BRCA2, ATM or CHEK2, such that testing of all genes is typically undertaken simultaneously as part of a small panel, for eligible patients.
- Constitutional (germline) genetic testing of PALB2 is available through the National Genomic Test Directory for individuals affected by breast, ovarian or pancreatic cancer who meet the eligibility criteria.
- PALB2 is also included in the gene panel test for individuals with confirmed Fanconi anaemia.
- The cancer risk associated with constitutional (germline) PALB2 variants is inherited in an autosomal dominant pattern. PALB2-associated Fanconi anaemia is inherited in an autosomal recessive manner.
- First-degree relatives of a carrier of a likely pathogenic/pathogenic variant in PALB2 are at 50% risk of carrying the familial variant.
- Carriers should be referred to clinical genetics services for genetic counselling and cascade screening.
- Although the risk of cancer in male carriers of PALB2 pathogenic/likely pathogenic variants is not markedly increased, cascade testing among male relatives is still encouraged given potential therapeutic implications if they do develop an associated cancer, and considering implications for their progeny, should they be found to be a carrier.
In addition to condition-specific information below, referral of affected patients to clinical genetics should be arranged to discuss onward management, family planning implications and cascade testing of at-risk relatives.
Female carriers of pathogenic PALB2 variants have a number of options for management of their increased breast cancer risk, including:
Very high risk (VHR) breast cancer screening
- Typically indicated from the age of 30, but may be considered from as young as 25 in patients with an estimated 10-year risk (calculated by CanRisk) of at least 8%.
- Screening consists of a combination of MRI and/or mammogram depending on age and breast density:
- Age 25/30-40: annual MRI
- Age 40-50: annual MRI and annual mammogram
- Age 50-70: annual mammogram
Risk-reducing breast surgery
- Many women may choose to undergo risk-reducing bilateral mastectomy, which is usually followed by immediate reconstruction where possible.
- The residual risk of breast cancer after risk-reducing prophylactic mastectomy is less than 5%.
- The survival advantage of surgery compared to surveillance is uncertain, but appears to be small, and diminishes rapidly with increasing age.
- Contralateral prophylactic mastectomy in a patient who has already been affected by breast cancer may be considered, and, if feasible, may be undertaken at the same time as therapeutic mastectomy.
- Contralateral prophylactic surgery will minimise the risk of a second primary breast cancer, but the risk of recurrence from the first breast cancer should be carefully considered when counselling the patient about the potential advantages of this surgery.
- Guidance from NICE (National Institute of Clinical Excellence) published in March 2017 recommends that chemoprevention with tamoxifen, raloxifene or anastrozole should be considered in women at increased risk of breast cancer based on their family history, after giving due consideration to potential contraindications and risks of adverse events.
- The role of chemoprophylaxis in prevention of PALB2-associated breast cancer has not been specifically explored.
Breast cancer screening is not recommended in male carriers of pathogenic PALB2 variants, but breast symptom awareness is encouraged.
- Ovarian cancer screening has not, as yet, been found to impact mortality from the disease.
- At present, the only proven method of minimising the risk of tubo-ovarian cancer in women at higher risk is to undergo risk-reducing ovarian surgery. Following this surgery, a residual risk of primary peritoneal cancer persists, which is estimated to be <4%.
- Considering that risks before age 50 are extremely low, the risks associated with premature menopause at that age outweigh potential benefit, such that risk-reducing ovarian surgery is not typically undertaken before that age unless there is a strong family history of early-onset ovarian cancer without an alternative aetiology. Considerations should also be given to fertility and family planning.
- In carriers of pathogenic variants in PALB2 who undergo risk-reducing bilateral salpingo-oophorectomy, hormone replacement therapy (HRT) is recommended to minimise risks associated with premature menopause, unless the patient has a preceding personal history of ER/PR-positive breast cancer.
- At the present time, as screening has not yet been proven to impact mortality from pancreatic cancer.
- The consensus from the UK Cancer Genetics Group is that screening for this type of cancer should not be offered outside of research studies.
- Patients should be counselled regarding modifiable risk factors (including smoking) and symptom awareness.
- The role of prostate cancer screening with PSA and MRI in carriers of PALB2 pathogenic/likely pathogenic variants is uncertain.
- Male carriers of such variants should be counselled regarding symptom awareness.
Family planning implications
The Human Fertilisation and Embryology Authority have approved the use of pre-implantation genetic testing for monogenic disorders (PGT-M) (previously known as pre-implantation genetic diagnosis, or PGD) for couples where one or both intended parents are carriers of a likely pathogenic or pathogenic variant in PALB2. It is best practice that discussions regarding PGT-M and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.
Other options may include prenatal testing (invasive, or non-invasive if the intended father is the carrier) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.
- NHS England: National Genomic Test Directory and eligibility criteria
- NICE: Familial breast cancer guidelines: classification, care and managing breast cancer and related risks in people with a family history of breast cancer
- OMIM (Online Mendelian Inheritance in Man): Online catalogue of human genes and genetic disorders
- Public Health England: Protocols for surveillance of women at very high risk of breast cancer
- UK Cancer Genetics Group: Very High Risk Breast Screening information
- Yang X, Leslie G, Doroszuk A and others. ‘Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families’. J Clin Oncol 2019: volume 38, issue 7, pages 674-685. doi: 10.1200/JCO.19.01907
- Breast Cancer Now: Genetic testing for altered breast cancer genes information
- PALB2 Interest Group: Information booklet for PALB2 carriers and their families