| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p12.2 | {Breast-ovarian cancer, familial, susceptibility to, 5} | 620442 | Autosomal dominant | 3 | PALB2 | 610355 |
A number sign (#) is used with this entry because of evidence that susceptibility to familial breast-ovarian cancer-5 (BROVCA5) results from heterozygous mutation in the PALB2 gene (610355) on chromosome 16p12.
Individuals with mutation in the PALB2 gene have an increased risk of developing breast or, to a lesser degree, ovarian cancer. In addition, PALB2 variants increase susceptibility to several other cancers, e.g., male breast cancer and pancreatic cancer (PNCA3; 613348) (Rahman et al., 2007; Norquist et al., 2018; Yang et al., 2020).
For a discussion of genetic heterogeneity of breast-ovarian cancer susceptibility, see BROVCA1 (604370).
For general discussions of breast cancer and ovarian cancer, see 114480 and 167000, respectively.
Reviews
Hamdan and Nowak (2023) reviewed the structure and function of the PALB2 gene, and its role in disease, including Fanconi anemia (FANCN; 610832), pancreatic cancer (PNCA3; 613348), and breast and ovarian cancer.
The transmission pattern of susceptibility to breast or ovarian cancer in the families reported by Rahman et al. (2007) and Foulkes et al. (2007) was consistent with autosomal dominant inheritance.
Because some Fanconi anemia-associated genes (see, e.g., BRCA1, 113705, and BRCA2, 600185) are also associated with breast cancer (see 114480), Rahman et al. (2007) investigated whether monoallelic mutations in the PALB2 gene, which encodes a BRCA2-interacting protein and causes a form of Fanconi anemia (FANCN; 610832), might also confer susceptibility to breast cancer. The authors sequenced the PALB2 gene in 923 individuals with breast cancer from familial breast cancer pedigrees in which mutations in BRCA1 or BRCA2 had not been found, and in 1,084 controls. They identified monoallelic truncating PALB2 mutations in 10 of 923 individuals with familial breast cancer and in none of the controls (p = 0.0004), and showed that such mutations confer a 2.3-fold higher risk of breast cancer. The results established PALB2 as a breast cancer susceptibility gene and further demonstrated the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition.
In 113 BRCA1/BRCA2 mutation-negative breast or breast-ovarian cancer families from northern Finland, Erkko et al. (2007) screened for germline PALB2 mutations and found that a frameshift mutation, c.1592delT (610355.0006), was present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of 1592delT in unselected breast cancer individuals revealed a roughly 4-fold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, 1 multigenerational prostate cancer family that segregated the 1592delT allele was observed. The authors concluded that these results indicated that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.
By sequencing PALB2 in a sample of 50 French Canadian women diagnosed with either early-onset or familial breast cancer at a single Montreal hospital, Foulkes et al. (2007) identified 1 clearly pathogenic mutation, Q775X (610355.0012), in a 54-year-old woman with invasive ductal breast cancer. Screening 356 unrelated French Canadian women with invasive ductal breast cancer diagnosed before age 50 years revealed 2 more carriers of the Q775X mutation, which was not found in 6,440 newborn controls (p = 0.003). Genotyping of 4 polymorphic microsatellite markers around the PALB2 gene revealed a common allele at each locus in the mutation carriers from each of the 3 families, suggesting that Q775X might be a founder mutation in the French Canadian population.
By screening the PALB2 gene, Tischkowitz et al. (2012) identified 5 pathogenic truncating mutations in 0.9% of 559 patients with contralateral breast cancer compared to no PALB2 mutations among 565 women with unilateral breast cancer used as controls (p = 0.04). Among the mutation carriers, the median ages of the first and second breast cancers were 46 and 55 years, respectively, and all probands had at least 1 first-degree relative with breast cancer, yielding a relative risk of 5.3 for carriers of a pathogenic PALB2 mutation. The frequency of rare missense mutations was similar in both groups, suggesting that rare PALB2 missense mutations do not strongly influence breast cancer risk.
In 747 women with breast cancer from Australian and New Zealander multiple-case breast cancer families, who were negative for BRCA1 and BRCA2 mutations, Teo et al. (2013) identified 2 nonsense mutations, 2 frameshift mutations, 10 missense variants, 8 synonymous variants, and 4 variants in intronic regions of the PALB2 gene. Of the 4 PALB2 null mutations, only 1 had not previously been reported. Most of the patients had high-grade invasive ductal carcinomas. Teo et al. (2013) concluded that approximately 1.5% (95% confidence interval, 0.6-2.4) of Australasian multiplex breast cancer families segregate null mutations in PALB2, most commonly W1038X (610355.0013).
Catucci et al. (2014) screened 575 probands from Italian breast cancer families negative for BRCA1/BRCA2 mutations and found that 2.1% had deleterious mutations in PALB2. One of these was a nonsense mutation that was recurrent in the province of Bergamo in northern Italy (Q343X; 610355.0011).
Antoniou et al. (2014) analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The risk of breast cancer for female PALB2 mutation carriers compared to the general population was 8 to 9 times as high among those younger than 40 years of age, 6 to 8 times as high among those 40 to 60 years of age, and 5 times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval, 9-20) by 50 years of age and 35% (95% confidence interval, 26-46) by 70 years of age. Breast cancer risk was also significantly influenced by birth cohort (p less than 0.001) and by other familial factors (p = 0.04). The absolute breast cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% confidence interval, 25-44) for those with no family history of breast cancer to 58% (95% confidence interval, 50-66) for those with 2 or more first-degree relatives with breast cancer at 50 years of age. Antoniou et al. (2014) calculated that PALB2 loss-of-function mutations account for approximately 2.4% of familial aggregation of breast cancer. Antoniou et al. (2014) concluded that their data suggested that the breast cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.
Responding to the paper by Antoniou et al. (2014), Lee and Ang (2014) screened for PALB2, BRCA1, and BRCA2 mutations using targeted capture methods and next-generation sequencing in 100 Asian patients enrolled from a risk-assessment clinic in Singapore. Protein-truncating mutations were detected in 3 (4%) of 78 patients who did not carry BRCA1 or BRCA2 mutations, and the mutations were validated by Sanger sequencing. In addition, deleterious PALB2 mutations were detected in a male patient with breast cancer and in a patient with ovarian cancer, underscoring the need to screen for PALB2 mutations in persons in whom BRCA2 mutations are suspected. Lee and Ang (2014) noted that the relatively high frequency of PALB2 mutations in their Asian population supported the recommendation by Antoniou et al. (2014) for PALB2 genetic testing in persons eligible for BRCA1 and BRCA2 mutation screening.
Norquist et al. (2018) performed targeted sequencing of DNA from 1,195 women with advanced ovarian cancer to detect mutations in homologous recombination repair (HRR) genes, and identified 6 unrelated women with germline PALB2 mutations, including 2 nonsense mutations, 2 frameshift mutations, 1 splice site mutation, and 1 duplication of exon 13. The authors noted that all 6 mutations had previously been reported in ovarian cancer patients (Norquist et al., 2016). Histology showed grade 3 serous carcinoma in 4 patients, mixed adenocarcinoma in 1 patient, and clear cell carcinoma in a patient diagnosed with primary peritoneal cancer. Analysis of progression-free survival and overall survival showed that hazard ratios for progression and death were significantly lower in cases with mutations in HRR genes; the effect was strongest for BRCA2 mutations and was similar for BRCA1 and non-BRCA HRR mutations.
Yang et al. (2020) analyzed data from 976 individuals from 524 families in 21 countries with germline pathogenic (truncating) PALB2 mutations (see, e.g., 610355.0001, 610355.0003-610355.0007, and 610355.0008-610355.0010), who were negative for mutation in the BRCA1/BRCA2 genes. In the main analysis, family members were followed from birth until age at diagnosis of first cancer; otherwise, they were followed until age at death, age at last follow-up, age at risk-reducing mastectomy or salpingo-oophorectomy, or age 80, whichever occurred first. The authors found associations between PALB2 pathogenic variants and risk of female breast cancer, ovarian cancer, pancreatic cancer, and male breast cancer. The breast cancer relative risk declined with age. On the basis of the combined data, the estimated risks to age 80 years were 53% for female breast cancer, 5% for ovarian cancer, 2-3% for pancreatic cancer, and 1% for male breast cancer. The authors concluded that the evidence from their study supported the inclusion of PALB2 in cancer gene panels.
Antoniou, A. C., Casadei, S., Heikkinen, T., Barrowdale, D., Pylkas, K., Roberts, J., Lee, A., Subramanian, D., De Leeneer, K., Fostira, F., Tomiak, E., Neuhausen, S. L., and 36 others. Breast-cancer risk in families with mutations in PALB2. New Eng. J. Med. 371: 497-506, 2014. [PubMed: 25099575] [Full Text: https://doi.org/10.1056/NEJMoa1400382]
Catucci, I., Peterlongo, P., Ciceri, S., Colombo, M., Pasquini, G., Barile, M., Bonanni, B., Verderio, P., Pizzamiglio, S., Foglia, C., Falanga, A., Marchetti, M., and 12 others. PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo. Genet. Med. 16: 688-694, 2014. [PubMed: 24556926] [Full Text: https://doi.org/10.1038/gim.2014.13]
Erkko, H., Xia, B., Nikkila, J., Schleutker, J., Syrjakoski, K., Mannermaa, A., Kallioniemi, A., Pylkas, K., Karppinen, S.-M., Rapakko, K., Miron, A., Sheng, Q., and 15 others. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446: 316-319, 2007. [PubMed: 17287723] [Full Text: https://doi.org/10.1038/nature05609]
Foulkes, W. D., Ghadirian, P., Akbari, M. R., Hamel, N., Giroux, S., Sabbaghian, N., Darnel, A., Royer, R., Poll, A., Fafard, E., Robidoux, A., Martin, G., Bismar, T. A., Tischkowitz, M., Rousseau, F., Narod, S. A. Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res. 9: R83, 2007. Note: Electronic Article. [PubMed: 18053174] [Full Text: https://doi.org/10.1186/bcr1828]
Hamdan, O., Nowak, K. M. Gene of the month: PALB2. J. Clin. Path. 76: 73-75, 2023. [PubMed: 36600573] [Full Text: https://doi.org/10.1136/jcp-2022-208461]
Lee, A. S. G., Ang, P. Breast-cancer risk in families with mutations in PALB2. (Letter) New Eng. J. Med. 371: 1650-1651, 2014. [PubMed: 25337758] [Full Text: https://doi.org/10.1056/NEJMc1410673]
Norquist, B. M., Brady, M. F., Harrell, M. I., Walsh, T., Lee, M. K., Gulsuner, S., Bernards, S. S., Casadei, S., Burger, R. A., Tewari, K. S., Backes, F., Mannel, R. S., and 9 others. Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: an NRG oncology/gynecologic oncology group study. Clin. Cancer Res. 24: 777-783, 2018. [PubMed: 29191972] [Full Text: https://doi.org/10.1158/1078-0432.CCR-17-1327]
Norquist, B. M., Harrell, M. I., Brady, M. F., Walsh, T., Lee, M. K., Gulsuner, S., Bernards, S. S., Casadei, S., Yi, Q., Burger, R. A., Chan, J. K., Davidson, S. A., Mannel, R. S., DiSilvestro, P. A., Lankes, H. A., Ramirez, N. C., King, M. C., Swisher, E. M., Birrer, M. J. Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol. 2: 482-490, 2016. [PubMed: 26720728] [Full Text: https://doi.org/10.1001/jamaoncol.2015.5495]
Rahman, N., Seal, S., Thompson, D., Kelly, P., Renwick, A., Elliott, A., Reid, S., Spanova, K., Barfoot, R., Chagtai, T., Jayatilake, H., McGuffog, L., Hanks, S., Evans, D. G., Eccles, D., The Breast Cancer Susceptibility Collaboration (UK), Easton, D. F., Stratton, M. R. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nature Genet. 39: 165-167, 2007. [PubMed: 17200668] [Full Text: https://doi.org/10.1038/ng1959]
Teo, Z. L., Park, D. J., Provenzano, E., Chatfield, C. A., Odefrey, F. A., Nguyen-Dumont, T., kConFab, Dowty, J. G., Hopper, J. L., Winship, I., Goldgar, D. E., Southey, M. C. Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families. Breast Cancer Res. 15: R17, 2013. Note: Electronic Article. [PubMed: 23448497] [Full Text: https://doi.org/10.1186/bcr3392]
Tischkowitz, M., Capanu, M., Sabbaghian, N., Li, L., Liang, X., Vallee, M. P., Tavtigian, S. V., Concannon, P., Foulkes, W. D., Bernstein, L., The WECARE Study Collaborative Group, Bernstein, J. L., Begg, C. B. Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum. Mutat. 33: 674-680, 2012. [PubMed: 22241545] [Full Text: https://doi.org/10.1002/humu.22022]
Yang, X., Leslie, G., Doroszuk, A., Schneider, S., Allen, J., Decker, B., Dunning, A. M., Redman, J., Scarth, J., Plaskocinska, I., Luccarini, C., Shah, M., and 107 others. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J. Clin. Oncol. 38: 674-685, 2020. [PubMed: 31841383] [Full Text: https://doi.org/10.1200/JCO.19.01907]