PALB2

Partner and localizer of BRCA2 (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).

• 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.

Approximately 1 in 700 people in the general population have a constitutional (germline) pathogenic variant in PALB2.

Routine constitutional (germline) testing of PALB2 in patients with cancer was introduced more recently than testing of BRCA1 and BRCA2. Consequently, our understanding of the full spectrum of pathogenic PALB2 variants and potential genotype-phenotype associations continues to evolve.

However, several recurrent variants have been identified in particular populations. Examples include PALB2 c.509_510delGA (p.Arg170IlefsTer14) and c.172_175delTTGT (p.Gln60ArgfsTer7) in the Polish population, c.1592delT (p.Leu531CysfsTer30) in the Finnish population, and c.3113G>A p.(Trp1038Ter), a recurrent pathogenic variant reported particularly in individuals of UK ancestry.

Another interesting example is PALB2 c.3549C>G (p.Tyr1183Ter), a recurrent pathogenic variant that introduces a premature stop codon very close to the end of the protein. Despite resulting in loss of only a small number of C-terminal amino acids, this variant disrupts a functionally important region of PALB2 and is associated with increased cancer risk. This illustrates that the predicted impact of a truncating variant depends not only on the amount of protein lost, but also on where in the protein the truncation occurs.

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 (to age 80) for carriers of pathogenic constitutional (germline) variants in PALB2 include:

*Note: Risks in transgender and gender non-confirming individuals may be modified by gender-affirming medication or surgery.

**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 less than 1%. before that age.
• The current largest study of PALB2-associated cancer risks, published in 2020, has not shown evidence of an increased risk of prostate cancer.
• 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 anomalies of the skeleton, eye or genitourinary system, short stature, progressive bone marrow failure and predisposition to haematological and solid tumours.

However, because pathogenic PALB2 variants are rare in the general population, routine testing of the reproductive partners of PALB2 carriers is not usually recommended. Partner testing may be considered where the likelihood of both partners carrying a pathogenic PALB2 variant is increased, for example because of shared ancestry from a population with a recognised founder variant, or a relevant family history.

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, BARD1, ATM, CHEK2, RAD51C or RAD51D, such that testing of all genes is typically undertaken simultaneously as part of a small panel, for eligible patients.

• Constitutional (germline) genomic 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 an individual with a likely pathogenic or pathogenic variant in PALB2 have a 50% chance of carrying the familial variant. 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.
• Referral of carriers to clinical genetics should be arranged to discuss onward management, family planning implications and cascade testing of at-risk relatives. All carriers of GPVs in PALB2 should also be enrolled to the National Inherited Cancer Predisposition Register (NICPR) (or equivalent in devolved nations), which is currently done through clinical genetics services.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

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.

Breast cancer

Female carriers

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 25
• Screening consists of a combination of MRI and/or mammogram depending on age and breast density:
  • Age 25–39: annual MRI
  • Age 40–50: annual MRI and annual mammogram
  • Age 51–70: annual mammogram

Risk-reducing breast surgery

• Some women may choose to undergo risk-reducing bilateral mastectomy, which is usually followed by immediate reconstruction where possible and according to patient choice.
• 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.

Risk-reducing medication

• Guidance from NICE published in March 2017 (last updated 2023) recommends that risk-reducing medication 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 risk-reducing medication in prevention of PALB2-associated breast cancer has not been specifically explored.
• Patients should be counselled regarding the impact of risk-reducing medication related to hormone driven cancers, the enrichment of triple negative disease in carriers of PALB2 variants should be acknowledged.

Male carriers

Breast cancer screening is not recommended in male carriers of pathogenic PALB2 variants, but breast symptom awareness is encouraged.

Tubo-ovarian cancer

• 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 less than 4%.
• Risk-reducing ovarian surgery is currently recommended to be considered for women whose individualised lifetime risk is 5% or greater (calculated by CanRisk).
• Considering the relatively cancer low risks before age 50, 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.

Pancreatic 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.

Prostate cancer

• 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.

• Pre-implantation genetic testing for monogenic or single-gene disorders (PGT-M) is available for certain genetic conditions associated with significant health risks. PGT-M can only be used for certain conditions, after approval by the UK Fertility Regulator (The Human Fertilisation and Embryology Authority). The HFEA decides approval by assessing severity, likelihood of inheritance, and evidence from affected families. It is important to recognise that HFEA approval is not automatic for these scenarios: the Statutory Approvals Committee will require a transparent, evidence-based justification demonstrating that the variant confers a sufficiently serious and well-characterised risk to meet regulatory criteria.
• With respect to family planning in carriers of variants associated with adult-onset cancer risk, decisions regarding the appropriateness of interventions such as PGT-M or prenatal testing with termination of affected embryos should be also be guided by available evidence, multidisciplinary input, and careful exploration of the family history and context.
• Other options for family planning may include adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.
• Discussions regarding PGT-M and other family planning options should be undertaken by a specialist genetic counsellor or clinical geneticist.

• PALB2 is a tumour suppressor gene with a role in the HRR pathway.
• Pathogenic variants in PALB2 are associated with high risk of breast cancer and increased risk in other cancers.
• When disease associated variants are identified in a patient they may choose to take risk-reducing measures including screening, surgery or chemoprophylaxis.
• Precision treatment options may be available for patients with cancers that have pathogenic PALB2 variants.

For clinicians

• 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
• PALB2 Interest Group: PALB2 mutation and cancer risks
• 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

References:

• Yang X, Leslie G, Doroszuk A and others. ‘Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families’. Journal of Clinical Oncologists 2019: volume 38, issue 7, pages 674–685. DOI: 10.1200/JCO.19.01907

For patients

• Breast Cancer Now: Genetic testing for altered breast cancer genes information