References

1. Wu S, Zhou J, Zhang K, et al.: Molecular Mechanisms of PALB2 Function and Its Role in Breast Cancer Management. Front Oncol 10: 301, 2020. [PMC free article: PMC7059202] [PubMed: 32185139]

References

1. Norquist BM, Harrell MI, Brady MF, et al.: Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2 (4): 482-90, 2016. [PMC free article: PMC4845939] [PubMed: 26720728]
2. Pritzlaff M, Summerour P, McFarland R, et al.: Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. Breast Cancer Res Treat 161 (3): 575-586, 2017. [PMC free article: PMC5241330] [PubMed: 28008555]
3. Lilyquist J, LaDuca H, Polley E, et al.: Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol 147 (2): 375-380, 2017. [PMC free article: PMC5801741] [PubMed: 28888541]
4. Weitzel JN, Neuhausen SL, Adamson A, et al.: Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. Cancer 125 (16): 2829-2836, 2019. [PMC free article: PMC7376605] [PubMed: 31206626]
5. Rizzolo P, Zelli V, Silvestri V, et al.: Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy. Int J Cancer 145 (2): 390-400, 2019. [PubMed: 30613976]
6. Deng M, Chen HH, Zhu X, et al.: Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. Int J Cancer 145 (6): 1517-1528, 2019. [PubMed: 30720863]
7. Fan X, Wynn J, Shang N, et al.: Penetrance of Breast Cancer Susceptibility Genes From the eMERGE III Network. JNCI Cancer Spectr 5 (4): , 2021. [PMC free article: PMC8346699] [PubMed: 34377931]
8. Fasching PA, Yadav S, Hu C, et al.: Mutations in BRCA1/2 and Other Panel Genes in Patients With Metastatic Breast Cancer -Association With Patient and Disease Characteristics and Effect on Prognosis. J Clin Oncol 39 (15): 1619-1630, 2021. [PMC free article: PMC8274805] [PubMed: 33780288]
9. Daly MB, Rosenthal E, Cummings S, et al.: The association between age at breast cancer diagnosis and prevalence of pathogenic variants. Breast Cancer Res Treat 199 (3): 617-626, 2023. [PMC free article: PMC10175307] [PubMed: 37084156]
10. Kurian AW, Hughes E, Handorf EA, et al.: Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women. JCO Precis Oncol 1: 1-12, 2017. [PubMed: 35172496]
11. Kotsopoulos J, Hathaway CA, Narod SA, et al.: Germline Mutations in 12 Genes and Risk of Ovarian Cancer in Three Population-Based Cohorts. Cancer Epidemiol Biomarkers Prev 32 (10): 1402-1410, 2023. [PMC free article: PMC10592229] [PubMed: 37493628]
12. Bucalo A, Conti G, Valentini V, et al.: Male breast cancer risk associated with pathogenic variants in genes other than BRCA1/2: an Italian case-control study. Eur J Cancer 188: 183-191, 2023. [PubMed: 37262986]
13. Morra A, Mavaddat N, Muranen TA, et al.: The impact of coding germline variants on contralateral breast cancer risk and survival. Am J Hum Genet 110 (3): 475-486, 2023. [PMC free article: PMC10027471] [PubMed: 36827971]
14. Suszynska M, Klonowska K, Jasinska AJ, et al.: Large-scale meta-analysis of mutations identified in panels of breast/ovarian cancer-related genes - Providing evidence of cancer predisposition genes. Gynecol Oncol 153 (2): 452-462, 2019. [PubMed: 30733081]
15. Rolfes M, Borde J, Möllenhoff K, et al.: Prevalence of Cancer Predisposition Germline Variants in Male Breast Cancer Patients: Results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancers (Basel) 14 (13): , 2022. [PMC free article: PMC9265404] [PubMed: 35805063]

Female Breast Cancer Risk Associated with PALB2 Pathogenic Variants

The association between PALB2 pathogenic variants and female breast cancer was first reported in 2007.[1] After the publication of several small studies, a 2014 report by the PALB2 Interest Group (PALB2-IG) (from 14 international research centers, involving 154 families with loss-of-function PALB2 pathogenic variants) confirmed that the risk range for female breast cancer in PALB2 overlapped with that of BRCA2.[2] Analysis of 311 women from these 154 families found that by age 70, absolute risk of female breast cancer was 33% (95% confidence interval [CI], 24%‒44%) for those without family histories of breast cancer and 58% (95% CI, 50%‒66%) for those with two or more first-degree relatives (FDRs) with early-onset breast cancer. A cohort effect was also observed, in which breast cancer risk was significantly higher in women from more recent birth cohorts. Thirty percent of women with available hormone receptor and human epidermal growth factor receptor 2 (HER2) statuses had triple-negative breast cancers.

In 2019, this study was updated and expanded to include 8,830 women in 524 families from 44 study centers in 21 countries.[3] Families included at least one member with a PALB2 pathogenic variant. Individuals with known BRCA1/2 pathogenic variants were excluded. The absolute risk of breast cancer was 16.9% (95% CI, 13.3%‒21.3%) by age 50 years and 52.8% (95% CI, 43.7%‒62.7%) by age 80 years. Like in the earlier study, both family history and birth cohort were significantly related to risk.

To avoid bias of studying only women with increased breast cancer risk, researchers sequenced PALB2 in 16,501 unselected BRCA1/2-negative breast cancer patients from 10 provinces in China.[4] This study found a PALB2 pathogenic variant prevalence of 0.97%, which is similar to prevalence estimates reported in other studies. The overall odds ratio (OR) for breast cancer risk in women with PALB2 pathogenic variants was 5.23 (95% CI, 2.84‒9.65). However, there was a significant association between breast cancer risk and age, with an OR of 10.09 (95% CI, 3.95‒25.70) for women age 30 years or younger and 5.06 (95% CI, 2.74‒9.43) for women older than 30 years. PALB2 carriers were more likely to have family histories of breast and/or ovarian cancer (20.63% vs.7.96% in noncarriers). These individuals were more likely to have larger tumors and positive axillary lymph nodes than controls. The Breast Cancer Association Consortium (BCAC) sequenced 34 suspected breast cancer susceptibility genes in 60,466 women with invasive breast cancer and 53,461 controls to refine estimates for breast cancer risk.[5] The OR for breast cancer risk in women with PALB2 pathogenic variants was 5.02 (95% CI, 3.73‒6.76). The OR was higher for estrogen receptor (ER)‒negative breast cancer.

Contralateral Breast Cancer Risk Associated with PALB2 Pathogenic Variants

Data on contralateral breast cancer (CBC) risk in PALB2 carriers are limited. Although there are limited data, both the CARRIERS Consortium and the BCAC have published similar findings.[6,7] The CARRIERS study included data from ten prospective studies of 15,104 women with genotype and phenotype data.[6] The overall hazard ratio (HR) for CBC in PALB2 carriers was 2.9 (95% CI, 1.4‒6.4). CBC risk was seen primarily in women with ER-negative disease. The HR for CBC in PALB2 carriers with ER-negative disease was 3.7 (95% CI, 1.5‒9.0). The 10-year cumulative risk of CBC was 7.9% overall and 19.7% in women with ER-negative breast cancer. CBC risk was significantly higher in African American women with ER-negative breast cancer, in whom the HR was 4.8 (95% CI, 1.4–16.8). CBC risk in this population was observed predominantly in women who were premenopausal when they were diagnosed with breast cancer. The BCAC report included 30,628 women from 34 studies.[7] The HR for CBC in women with PALB2 pathogenic variants was 2.67 (95% CI, 1.35‒5.35). PALB2 carriers had poorer survival when compared with noncarriers, but this association was not significant when it was adjusted to include tumor characteristics.

Male Breast Cancer Risk Associated with PALB2 Pathogenic Variants

Risk of male breast cancer in the general population is 0.1%. However, this cancer clusters in families with breast cancer cases. While there are few studies on pathogenic variants identified in men diagnosed with breast cancer, several reports have detected PALB2 pathogenic variants in this population. Data on 708 men with breast cancer who underwent testing at one genetic testing lab found an OR of 6.6 (95% CI, 1.7‒21.1) for breast cancer in men with a PALB2 pathogenic variant, although the number of individuals with PALB2 pathogenic variants in this study was small.[8] A large case-control study from Italy that included 767 BRCA1/2-negative men with breast cancer found an OR of 7.28 (95% CI, 1.17‒45.42) for male breast cancer in men with PALB2 pathogenic variants.[9] Like in sporadic male breast cancer, most tumors in men with non-BRCA1/2 pathogenic variants were invasive ductal carcinomas that were ER-positive, progesterone receptor‒positive, and HER2-negative. Similarly, the PALB2-IG study of 524 families with PALB2 pathogenic variants reported a relative risk (RR) of 7.34 (95% CI, 1.28‒42.19) for male breast cancer.[3] Despite small numbers, estimates of male breast cancer risk associated with PALB2 are consistent across studies. PALB2 is emerging as the second-most commonly mutated gene in male breast cancer, after BRCA2.

Pancreatic Cancer Risk Associated with PALB2 Pathogenic Variants

A study first reported a PALB2 pathogenic variant in an individual with familial pancreatic cancer in 2009 using exome sequencing.[10] In subsequent studies of individuals with exocrine pancreatic cancer, PALB2 pathogenic variants were found in 2% to 4% of participants.[11,12] In the PALB2-IG study (with 524 PALB2 families), the RR was 2.4 (95% CI, 1.24‒4.50) for pancreatic cancer when PALB2 pathogenic variants were present.[3] In individuals with PALB2 pathogenic variants, the absolute lifetime risk of pancreatic cancer is estimated to be between 5% and 10%.

Ovarian Cancer Risk Associated with PALB2 Pathogenic Variants

Although data on the association between PALB2 pathogenic variants and ovarian cancer are mixed, there is growing acknowledgement that ovarian cancer risk may be moderately increased in PALB2 carriers. Ovarian cancer risk is further increased in women who are diagnosed with ovarian cancer at young ages and in those with family histories of breast/ovarian cancers.

A University of Washington study ascertained the frequency of PALB2 pathogenic variants in patients with ovarian cancer.[13] Patients were unselected for age/family history and were enrolled through a university biobank and two Gynecologic Oncology Group (GOG) clinical trials for advanced ovarian cancer. The OR for ovarian cancer was 10.2 (95% CI, 2.2‒47.0). A similar study on the frequency of pathogenic variants from multigene panel testing in a series of clinically ascertained ovarian cancer cases (participants were referred to one genetic testing lab) found a standardized risk ratio of 3.08 (95% CI, 1.93‒4.67) for PALB2.[14] The authors speculated that this association was driven by a strong association between PALB2 and breast cancer risk, since participants were 3.5-times more likely to have personal or family histories of breast cancer when compared with reference controls. Similar data from a different genetic testing lab reported an OR of 1.60 for ovarian cancer (95% CI, 0.98‒2.60), which did not meet statistical significance.[15] Researchers sequenced the coding regions of 54 candidate genes in 6,385 women with invasive ovarian cancer and 6,115 controls with broad European ancestry from 19 studies (mostly case-control studies).[16] This study found that PALB2 pathogenic variants were associated with a moderate risk of high-grade serous ovarian cancer (OR, 2.60; 95% CI, 1.45‒4.64; P = .0013). The cumulative absolute risk of ovarian cancer in PALB2 carriers by age 80 years was 3.2% (95% CI, 1.8%‒5.7%). Similarly, the PALB2-IG study found an estimated RR of 2.91 (95% CI, 1.40‒6.04) for ovarian cancer in PALB2 carriers and an absolute lifetime ovarian cancer risk of approximately 5%.[3] The aforementioned meta-analysis of 48 studies found an OR of 2.13 for ovarian cancer.[17]

Other Cancer Risks Associated with PALB2 Pathogenic Variants

PALB2 pathogenic variants have been described in colorectal, gastric, prostate, and other cancers.[3] However, PALB2's contribution to risk in these cancer types has not yet been confirmed. For more information about research on PALB2 and gastric cancer risk, see the Other Genes Associated With Gastric Cancer section in Genetics of Gastric Cancer.

References

1. Rahman N, Seal S, Thompson D, et al.: PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39 (2): 165-7, 2007. [PMC free article: PMC2871593] [PubMed: 17200668]
2. Antoniou AC, Casadei S, Heikkinen T, et al.: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371 (6): 497-506, 2014. [PMC free article: PMC4157599] [PubMed: 25099575]
3. Yang X, Leslie G, Doroszuk A, et al.: Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. J Clin Oncol 38 (7): 674-685, 2020. [PMC free article: PMC7049229] [PubMed: 31841383]
4. Zhou J, Wang H, Fu F, et al.: Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing. Cancer 126 (14): 3202-3208, 2020. [PMC free article: PMC7384117] [PubMed: 32339256]
5. Dorling L, Carvalho S, Allen J, et al.: Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med 384 (5): 428-439, 2021. [PMC free article: PMC7611105] [PubMed: 33471991]
6. Yadav S, Boddicker NJ, Na J, et al.: Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. J Clin Oncol 41 (9): 1703-1713, 2023. [PMC free article: PMC10022863] [PubMed: 36623243]
7. Morra A, Mavaddat N, Muranen TA, et al.: The impact of coding germline variants on contralateral breast cancer risk and survival. Am J Hum Genet 110 (3): 475-486, 2023. [PMC free article: PMC10027471] [PubMed: 36827971]
8. Pritzlaff M, Summerour P, McFarland R, et al.: Male breast cancer in a multi-gene panel testing cohort: insights and unexpected results. Breast Cancer Res Treat 161 (3): 575-586, 2017. [PMC free article: PMC5241330] [PubMed: 28008555]
9. Bucalo A, Conti G, Valentini V, et al.: Male breast cancer risk associated with pathogenic variants in genes other than BRCA1/2: an Italian case-control study. Eur J Cancer 188: 183-191, 2023. [PubMed: 37262986]
10. Jones S, Hruban RH, Kamiyama M, et al.: Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324 (5924): 217, 2009. [PMC free article: PMC2684332] [PubMed: 19264984]
11. Slater EP, Langer P, Niemczyk E, et al.: PALB2 mutations in European familial pancreatic cancer families. Clin Genet 78 (5): 490-4, 2010. [PubMed: 20412113]
12. Hofstatter EW, Domchek SM, Miron A, et al.: PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer 10 (2): 225-31, 2011. [PMC free article: PMC3836668] [PubMed: 21365267]
13. Norquist BM, Harrell MI, Brady MF, et al.: Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2 (4): 482-90, 2016. [PMC free article: PMC4845939] [PubMed: 26720728]
14. Lilyquist J, LaDuca H, Polley E, et al.: Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol 147 (2): 375-380, 2017. [PMC free article: PMC5801741] [PubMed: 28888541]
15. Kurian AW, Hughes E, Handorf E: Association of ovarian cancer (OC) risk with mutations detected by multiple-gene germline sequencing in 95,561 women. [Abstract] J Clin Oncol 34 (Suppl 15): A-5510, 2016. Also available online. Last accessed November 7, 2024.
16. Song H, Dicks EM, Tyrer J, et al.: Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer. J Med Genet 58 (5): 305-313, 2021. [PMC free article: PMC8086250] [PubMed: 32546565]
17. Suszynska M, Klonowska K, Jasinska AJ, et al.: Large-scale meta-analysis of mutations identified in panels of breast/ovarian cancer-related genes - Providing evidence of cancer predisposition genes. Gynecol Oncol 153 (2): 452-462, 2019. [PubMed: 30733081]

References

1. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2025 . Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2025. Available online with free registration. Last accessed October 30, 2024. [PubMed: 33406487]
2. Hanson H, Kulkarni A, Loong L, et al.: UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2. J Med Genet 60 (5): 417-429, 2023. [PMC free article: PMC10176381] [PubMed: 36411032]

Breast Cancer Prognosis in PALB2 Carriers

A prospective cohort study of 12,529 women with invasive breast cancer in Poland first reported an excess of triple-negative breast cancer (TNBC) in PALB2 carriers when compared with noncarriers.[1] In this study, the hazard ratio (HR) for death associated with PALB2 pathogenic variants was 2.19 (95% confidence interval, 1.59‒3.02). However, this HR pertained to women with tumors larger than 2 cm. In a study of 16,501 unselected BRCA1/2-negative breast cancer patients from China, PALB2 carriers were significantly more likely to have TNBCs than noncarriers (22.83% vs. 13.56%, respectively).[2] PALB2 carriers had larger tumors, more positive axillary lymph nodes, and more contralateral breast cancers. Other studies reported that PALB2 carriers had TNBC rates ranging from 30% to 40%.[3] A large population-based study in China observed a significantly shorter overall survival in PALB2 carriers with breast cancer than in noncarriers.[4]

References

1. Cybulski C, Kluźniak W, Huzarski T, et al.: Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol 16 (6): 638-44, 2015. [PubMed: 25959805]
2. Zhou J, Wang H, Fu F, et al.: Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing. Cancer 126 (14): 3202-3208, 2020. [PMC free article: PMC7384117] [PubMed: 32339256]
3. Antoniou AC, Casadei S, Heikkinen T, et al.: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371 (6): 497-506, 2014. [PMC free article: PMC4157599] [PubMed: 25099575]
4. Deng M, Chen HH, Zhu X, et al.: Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. Int J Cancer 145 (6): 1517-1528, 2019. [PubMed: 30720863]

References

1. Tischkowitz M, Balmaña J, Foulkes WD, et al.: Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 23 (8): 1416-1423, 2021. [PubMed: 33976419]
2. Toss A, Ponzoni O, Riccò B, et al.: Management of PALB2-associated breast cancer: A literature review and case report. Clin Case Rep 11 (8): e7747, 2023. [PMC free article: PMC10444947] [PubMed: 37621724]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about PALB2. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for PALB2 are:

• Doreen Agnese, MD (The Ohio State University)
• Ilana Cass, MD (Dartmouth-Hitchcock Medical Center)
• Lee-may Chen, MD (UCSF Helen Diller Family Comprehensive Cancer Center)
• Mary B. Daly, MD, PhD (Fox Chase Cancer Center)
• Megan Frone, MS, CGC (National Cancer Institute)
• Jessica Hatton , MS, CGC (National Cancer Institute)
• Joanne Kotsopoulos, PhD (University of Toronto and Women's College Hospital)
• Tuya Pal, MD, FACMG, FCCMG (Vanderbilt-Ingram Cancer Center)
• Padma Sheila Rajagopal, MD, MPH, MSC (National Cancer Institute)

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PDQ® Cancer Genetics Editorial Board. PDQ PALB2. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/publications/pdq/information-summaries/genetics/palb2-hp-pdq. Accessed <MM/DD/YYYY>.

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