Alternative titles; symbols
HGNC Approved Gene Symbol: PALB2
Cytogenetic location: 16p12.2 Genomic coordinates (GRCh38): 16:23,603,165-23,641,310 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p12.2 | {Breast-ovarian cancer, familial, susceptibility to, 5} | 620442 | Autosomal dominant | 3 |
| {Pancreatic cancer, susceptibility to, 3} | 613348 | Autosomal dominant | 3 | |
| Fanconi anemia, complementation group N | 610832 | 3 |
PALB2 colocalizes with BRCA2 (600185) in nuclear foci, promotes its localization and stability in nuclear structures, and enables its recombinational repair and checkpoint functions (Xia et al., 2006).
Using mass spectrometric analysis to identify proteins that immunoprecipitated with BRCA2 from HeLa cell extracts, followed by RT-PCR, Xia et al. (2006) cloned PALB2. The deduced 1,186-amino acid protein has a calculated molecular mass of about 130 kD. PALB2 contains an N-terminal prefoldin (see 604897)-like domain and 2 C-terminal WD40-like repeats. Immunohistochemical staining of a human osteosarcoma cell line localized PALB2 with BRCA2 in S-phase foci.
Xia et al. (2007) and Reid et al. (2007) determined that the PALB2 gene comprises 13 exons.
Xia et al. (2006) stated that the PALB2 gene maps to chromosome 16p12.
By coimmunoprecipitation analysis, Xia et al. (2006) found that PALB2 and BRCA2 coimmunoprecipitated from lysates of several human cell lines. Differential extraction showed that BRCA2 and PALB2 were associated with stable nuclear structures and were likely complexed in chromatin. Immunodepletion of BRCA2 codepleted much of PALB2, whereas immunodepletion of PALB2 codepleted nearly all BRCA2. BRCA1 (113705) abundance was not significantly affected. S-phase foci containing BRCA2 and PALB2 underwent dispersal and refocusing after ionizing radiation, suggesting that, like BRCA2, PALB2 participates in DNA damage response. Depletion of PALB2 by small interfering RNA largely abrogated BRCA2 focus formation. No BRCA2 foci were observed even after ionizing radiation in PALB2-depleted cells. PALB2 appeared to promote stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation. Multiple germline BRCA2 missense mutations identified in breast cancer patients appeared to disrupt PALB2 binding and disable the homologous recombination-based DNA double-strand break repair function of BRCA2.
Orthwein et al. (2015) reported that the cell cycle controls the interaction of BRCA1 (113705) with PALB2-BRCA2 to constrain BRCA2 function to the S/G2 phases in human cells. Orthwein et al. (2015) found that the BRCA1-interaction site on PALB2 is targeted by an E3 ubiquitin ligase composed of KEAP1 (606016), a PALB2-interacting protein, in complex with cullin-3 (603136)-RBX1 (603814). PALB2 ubiquitylation suppresses its interaction with BRCA1 and is counteracted by the deubiquitylase USP11 (300050), which is itself under cell-cycle control. Restoration of the BRCA1-PALB2 interaction combined with the activation of DNA-end resection is sufficient to induce homologous recombination in G1, as measured by RAD51 (179617) recruitment, unscheduled DNA synthesis, and a CRISPR-Cas9-based gene-targeting assay. Orthwein et al. (2015) concluded that the mechanism prohibiting homologous recombination in G1 minimally consists of the suppression of DNA-end resection coupled with a multistep block of the recruitment of BRCA2 to DNA damage sites that involves the inhibition of BRCA1-PALB2-BRCA2 complex assembly.
Fanconi Anemia, Complementation Group N
Xia et al. (2007) identified a patient who appeared to represent a theretofore unrecognized Fanconi anemia complementation group, designated subtype N (FANCN; 610832). This individual showed normal monoubiquitination of FANCD2 (227646) and no detected pathogenic alterations in BRCA2 (600185) or FANCJ (609054). Lack of full-length PALB2 protein and the reduced amount of BRCA2 suggested the existence of sequence alterations in the gene encoding PALB2, since PALB2 interacts with BRCA2 and is important in determining the localization and stability of BRCA2 in the nucleus. In a phenotypically reverted (mitomycin C-resistant) subline of patient lymphoblasts, a normal amount of BRCA2 without the reappearance of PALB2 was found. Xia et al. (2007) sequenced the genomic DNA as well as cDNA from this patient and found an apparently homozygous or hemizygous nonsense mutation in exon 4, leading to the amino acid change Y551X (610355.0001). As this mutation was detected only in the mother, Xia et al. (2007) suspected that the patient was a compound heterozygote for a deletion on the paternal allele in the region of the exon 4 mutation. Multiplex ligation-dependent probe amplification (MLPA) analysis confirmed an intragenic deletion present on the paternal allele (610355.0002). cDNA sequencing and MLPA analysis uncovered a second sequence alteration in revertant cells that restored part of the PALB2 open reading frame (ORF) that could explain recovery of PALB2 activity. The corrective alteration deleted the premature stop-containing exon 4 from the mRNA, resulting in an in-frame fusion of exons 3 and 5. Subsequent genomic sequencing showed a 5,962-bp deletion between Alu repeats in introns 3 and 4 of the maternal allele that was probably generated by a spontaneous Alu-mediated recombination. Further studies showed that a shortened PALB2 protein with a large internal deletion was functional, whereas the N-terminal 550 residues of PALB2 could not function alone.
Reid et al. (2007) demonstrated pathogenic mutations in PALB2 in 7 families with Fanconi anemia and cancer in early childhood, demonstrating that biallelic PALB2 mutations cause a novel subtype of Fanconi anemia, FA-N, and, similar to biallelic BRCA2 mutations, confer a high risk of childhood cancer.
Adult Cancer Susceptibility
As PALB2 is critical for the function of BRCA2 in DNA repair and tumor suppression, it could, in principle, also be a tumor suppressor protein. Xia et al. (2007) noted that several family members of the individual they studied with FANCN indeed developed tumors, and some of these tumors fell into the BRCA2 tumor spectrum: cancers of the esophagus, breast, prostate, and stomach. Reid et al. (2007) suggested that, given the intimate functional links between PALB2 and BRCA2 and the similar phenotypes associated with biallelic mutations in the genes that encode them, it seemed plausible that monoallelic PALB2 mutations could confer susceptibility to adult cancer.
Breast-Ovarian Cancer, Familial, Susceptibility to, 5
To investigate whether monoallelic PALB2 mutations confer susceptibility to breast cancer (BROVCA5; 620442), Rahman et al. (2007) sequenced the PALB2 gene in 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.
Erkko et al. (2007) screened for PALB2 mutations in Finland and found that a frameshift mutation, c.1592delT (see 610355.0006), is 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 c.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. Erkko et al. (2007) 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.
Foulkes et al. (2007) sequenced PALB2 in a sample of 50 French Canadian women diagnosed with either early-onset or familial breast cancer at a single Montreal hospital. The variants identified in this sample were then screened in 356 additional women with breast cancer diagnosed before age 50 years. Foulkes et al. (2007) identified a single protein-truncating mutation (Q775X; 610355.0012) in the PALB2 gene in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and was not present in any of 6,440 newborn controls (p = 0.003).
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, who were 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.
Teo et al. (2013) screened PALB2 for mutations in multiplex breast cancer families from Australia and New Zealand who were negative for BRCA1 and BRCA2 mutations. The authors identified 2 nonsense mutations, 2 frameshift mutations, 10 missense variants, 8 synonymous variants, and 4 variants in intronic regions. Of the 4 PALB2 null mutations, only 1 had not been previously 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 to 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 to 20) by 50 years of age and 35% (95% confidence interval, 26 to 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 to 44) for those with no family history of breast cancer to 58% (95% confidence interval, 50 to 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.
Lee and Ang (2014) responded to the paper by Antoniou et al. (2014). They 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.
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). 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 strongest for BRCA2 mutations and was similar for BRCA1 and non-BRCA HRR mutations, including PALB2.
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. 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 to 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.
Pancreatic Cancer Susceptibility 3
In a patient with pancreatic cancer (PNCA3; 613348) whose tumor DNA had previously been sequenced, Jones et al. (2009) found 15,461 germline variants among 20,661 coding genes screened. Three genes, including PALB2, carried variants in both germline and tumor DNA. PALB2 was considered the best candidate because of the rarity of terminating PALB2 mutations in healthy individuals and because PALB2 had previously been implicated in breast cancer and Fanconi anemia. This patient harbored a germline deletion of 4 basepairs that resulted in a frameshift (610355.0007). The authors then sequenced the PALB2 gene in a cohort of 96 patients with familial pancreatic cancer and identified truncating mutations (610355.0008-610355.0010) in 3 unrelated patients. Of the 4 families with pancreatic cancer in which Jones et al. (2009) identified a PALB2 stop mutation, 3 also had multiple family members with breast cancer, and there were at least 2 other types of cancer present in all 4 families.
Jones et al. (2009) concluded that PALB2 appears to be the second most commonly mutated gene for hereditary pancreatic cancer. The most commonly mutated gene is BRCA2, whose protein product is a binding partner for the PALB2 protein.
Rantakari et al. (2010) found that Palb2 +/- mice were normal in appearance and fertile; they lacked macroscopic tumors from birth through final follow-up at age 8 months. Homozygous Palb2 -/- mouse embryos died prior to embryonic day 9.5. The mutant embryos were small and developmentally retarded and displayed defective mesoderm differentiation after gastrulation. In Palb2 -/- embryos, the expression of cyclin-dependent kinase inhibitor p21 (CDKN1A; 116899) was increased, and Palb2 -/- blastocysts showed a growth defect in vitro. Hence, the phenotype observed in the early development of Palb2 -/- mouse embryos resembled those in Brca1 (113705) and Brca2 (600185) knockout mice. The authors concluded that the PALB2 gene plays an important role in early mouse embryogenesis, and that the protein is essential for cell proliferation, acting in the same cellular processes as BRCA1 and BRCA2.
Fanconi Anemia, Complementation Group N
In an infant with Fanconi anemia of complementation group N (FANCN; 610832), Xia et al. (2007) found compound heterozygosity for 2 mutations in the PALB2 gene: an 1802T-A transversion in exon 4 that resulted in premature termination of the protein (Y551X) on the maternal allele, and an intragenic deletion inherited from the father (610355.0002).
Breast-Ovarian Cancer, Familial, Susceptibility to, 5
In a family with at least 1 case of breast and ovarian cancer (BROVCA5; 620442), Yang et al. (2020) identified heterozygosity for the Y551X mutation in the PALB2 gene.
For discussion of the intragenic deletion in the PALB2 gene (ex2-6del) that was found in compound heterozygous state in a patient with Fanconi anemia of complementation group N (FANCN; 610832) by Xia et al. (2007), see 610355.0001.
Fanconi Anemia, Complementation Group N
In 2 separate families, one British and the other North American, Reid et al. (2007) found that Fanconi anemia of complementation group N (FANCN; 610832) was associated with a 3549C-G transversion in exon 13 of the PALB2 gene. The transversion resulted in substitution of a termination codon for tyrosine at codon 1183 (Y1183X). In the British family, the Y1183X mutation was present in compound heterozygous state with a Q988X mutation (610355.0004); in the North American family, with a frameshift mutation (610355.0005).
Breast-Ovarian Cancer, Familial, Susceptibility to, 5
Rahman et al. (2007) found the 3549C-G mutation in heterozygous state in 3 unrelated women with breast cancer (BROVCA5; 620442), all from families with multiple cases of breast cancer. One of the woman also had melanoma.
Yang et al. (2020) identified the Y1183X mutation in the PALB2 gene in 18 families, all of which had at least 1 case of breast cancer. In addition, there was at least 1 case of ovarian cancer in 7 of the families, and of pancreatic cancer in 4 families. Colon cancer was also present in 3 families and prostate cancer in 2, and 'other' (unspecified) cancers were present in 15 of the families.
Fanconi Anemia, Complementation Group N
In a British family with Fanconi anemia, complementation group N (FANCN; 610832), Reid et al. (2007) found a 2962C-T transition in exon 9 of the PALB2 gene, resulting in premature termination of the protein (Q988X), in compound heterozygosity with a second premature termination mutation (610355.0003). The authors noted that the maternal grandmother in this family developed breast cancer at age 52 years, and suggested that patients with familial breast cancer should be screened for mutation in PALB2 (see BROVCA5, 620442).
Breast-Ovarian Cancer, Familial, Susceptibility to, 5
Yang et al. (2020) identified the Q988X mutation in the PALB2 gene in a family with breast cancer as well as 'other' (unspecified) cancers.
Fanconi Anemia, Complementation Group N
In a North American family with Fanconi anemia complementation group N (FANCN; 610832), Reid et al. (2007) found a 1-bp deletion, c.3116delA (N1039fs), in exon 11 of the PALB2 gene in compound heterozygosity with a premature termination mutation (610355.0003).
Breast-Ovarian Cancer, Familial, Susceptibility to, 5
In 3 individuals with breast cancer (BROVCA5; 620442) from unrelated families with familial breast cancer, Rahman et al. (2007) found a frameshift mutation in the PALB2 gene: c.3116delA, Asn1039fs.
In a patient with familial pancreatic cancer, Jones et al. (2009) identified germline heterozygosity for the c.3116delA variant in the PALB2 gene. The proband's mother and his maternal grandmother had pancreatic cancer, and his mother and a maternal aunt also had breast cancer. In addition, the proband had prostate cancer.
Yang et al. (2020) identified the PALB2 c.3116delA variant, causing a frameshift predicted to result in a premature termination codon (Asn1039IlefsTer2), in 9 families with breast cancer, 1 of which also had at least 1 case of ovarian cancer and another had 1 case of pancreatic cancer. In addition, prostate cancer was present in 2 families, colon cancer in 1 family, and 'other' (unspecified) cancers were present in 5 of the families.
Erkko et al. (2007) screened probands from 113 BRCA1/BRCA2 mutation-negative breast or breast-ovarian cancer (BROVC5; 620442) families from northern Finland. A 1-bp deletion of thymidine at nucleotide 1592 of the PALB2 coding sequence was detected in 3 probands but only in 6 of 2,501 controls, giving an odds ratio of 11.3 and a 95% confidence interval of 1.8 to 57.8. The alteration should result in frameshift at leu531, with the new open reading frame progressing for 28 codons before termination. The mutation was also found in 18 of 1,918 Finnish unselected breast cancer cases (odds ratio of 3.94, 95% CI 1.5-12.1). The authors noted that all families studied showed other forms of cancer, including pancreatic, stomach, colorectal, and endometrial cancers, and leukemia.
Yang et al. (2020) identified the PALB2 c.1592delT mutation, causing a frameshift predicted to result in a premature termination codon (Leu531CysfsTer30), in 49 families, 48 of which had at least 1 case of breast cancer. In addition, there was at least 1 case of ovarian cancer in 6 of the families, and of pancreatic cancer in 7 families. Prostate cancer was also present in 8 of the families, colon cancer in 4, and 'other' (unspecified) cancers were present in 33 of the families.
In a patient with pancreatic cancer (PNCA3; 613348) whose tumor DNA had previously been sequenced, Jones et al. (2009) found a heterozygous germline deletion of 4 basepairs in the PALB2 gene, TTGT approximately at nucleotide 172 in exon 3, that produced a frameshift at codon 58. The pancreatic cancer had also somatically acquired a transition mutation, a C-to-T transition at a canonical splice site for exon 10 (IVS10+2). The proband had a sister with pancreatic cancer, and another sister, their mother, and a maternal aunt all had breast cancer. Other cancers reported in the family included gastrointestinal carcinoma and melanoma.
Yang et al. (2020) identified the PALB2 c.172delTTGT mutation, causing a frameshift predicted to result in a premature termination codon (Gln60ArgfsTer7), in 18 families, all of which had at least 1 case of breast cancer. In addition, there was at least 1 case of ovarian cancer in 2 of the families, of male breast cancer in 1 family, and of pancreatic cancer in 4 families. Colon cancer was also present in 4 families and prostate cancer in 3, and 'other' (unspecified) cancers were present in 14 of the families.
In a patient with familial pancreatic cancer (PNCA3; 613348), Jones et al. (2009) identified a heterozygous germline G-to-T transversion at the -1 position of intron 5 of the PALB2 gene. This mutation affects splicing. The proband had both pancreatic and breast cancer, as did 1 of her sisters; another sister had only breast cancer, and their maternal grandmother and a maternal great aunt also had breast cancer. Other cancers reported in the family included stomach, colon, lung, and kidney.
In 2 brothers with familial pancreatic cancer (PNCA3; 613348), Jones et al. (2009) identified a heterozygous germline c.3256C-T transition in exon 12 of the PALB2 gene. Their father had stomach and prostate cancer.
Yang et al. (2020) identified the c.3256C-T transition in the PALB2 gene, resulting in an arg1086-to-ter (R1086X) substitution, in 10 families, 9 of which had at least 1 case of breast cancer. In addition, there was at least 1 case of ovarian cancer in 3 of the families, and of pancreatic cancer in 1 family. Colon cancer was also present in 2 families and prostate cancer in 2, and 'other' (unspecified) cancers were present in 6 of the families.
In 3 Italian women with breast cancer (BROVCA5; 620442), all from multiplex families from the province of Bergamo in northern Italy, Catucci et al. (2014) identified heterozygosity for a c.1027C-T transition in exon 4 of the PALB2 gene, resulting in a gln343-to-ter (Q343X) substitution. No carriers of this mutation were identified among 332 BRCA-negative breast cancer patients recruited in Milan, but 6 carriers (5.3%) were identified among 113 BRCA-negative breast cancer patients recruited in Bergamo. An additional 2 carriers (0.4%) were identified among 477 female blood donors from Bergamo (p less than 0.01, Fisher exact test). In the 9 Italian families in which the proband with breast cancer carried the Q343X mutation, there were multiple other family members with breast cancer as well as individuals with other cancers, including pancreatic, brain, larynx, lung, intestinal tract, uterus, prostate, leukemia, Hodgkin lymphoma, and osteosarcoma.
Yang et al. (2020) identified the Q343X mutation in the PALB2 gene in 8 families, all of which had at least 1 case of breast cancer. In addition, there was at least 1 case of pancreatic cancer in 2 of the families. Colon cancer was also present in 2 families and prostate cancer in 1, and 'other' (unspecified) cancers were present in all 8 families.
In a French Canadian woman with familial breast-ovarian cancer-5 (BROVCA5; 620442) who had been diagnosed with invasive ductal breast cancer at age 54, Foulkes et al. (2007) identified a c.2323C-T transition in the PALB2 gene, resulting in a gln775-to-ter (Q775X) substitution. This variant was present in 2 of 356 other breast cancer patients diagnosed prior to age 50 years and was not present in 6,440 newborn controls (p = 0.003). Foulkes et al. (2007) stated that this mutation accounts for 0.5% of early-onset breast cancer cases in French Canadian women and appears to have a single origin due to a founder effect in the population.
Yang et al. (2020) identified the Q775X mutation in the PALB2 gene in 19 families, 18 of which had at least 1 case of breast cancer. In addition, there was at least 1 case of ovarian cancer in 3 of the families, of male breast cancer in 1 family, and of pancreatic cancer in 5 families. Colon cancer was also present in 6 families and prostate cancer in 4, and 'other' (unspecified) cancers were present in 16 of the families.
In probands from 2 families with breast-ovarian cancer-5 (BROVCA5; 620442), Rahman et al. (2007) identified a c.3113G-A transition in the PALB2 gene that resulted in a trp1038-to-ter (W1038) substitution. One proband had been diagnosed at the age of 43 years and had 3 relatives with breast cancer; the other proband had been diagnosed at the age of 49 years and had 4 affected relatives.
In 8 of 747 multiplex breast cancer families from Australia and New Zealand, Teo et al. (2013) identified segregation of the c.3113G-A transition in the PALB2 gene. The median age of diagnosis in those carrying this mutation was 48.5 years, with a range of 32 to 79 years. Teo et al. (2013) identified 2 alternative transcripts in RT-PCR assays of the c.3113G-A mutation. One involved the deletion of exon 10 (117 bp; r.2997_3113del, Gly1000_Gly1038del), and the other a 31-bp deletion in exon 10 (r.3083_3113del, Gly1028fsTer3).
Yang et al. (2020) identified the W1308X mutation in the PALB2 gene in 61 families, 58 of which had at least 1 case of breast cancer. In addition, there was at least 1 case of ovarian cancer in 9 of the families, of male breast cancer in 2 families, and of pancreatic cancer in 1 family. Colon cancer was also present in 19 families and prostate cancer in 13, and 'other' (unspecified) cancers were present in 42 of the families.
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]
Jones, S., Hruban, R. H., Kamiyama, M., Borges, M., Zhang, X., Parsons, D. W., Lin, J. C.-H., Palmisano, E., Brune, K., Jaffee, E. M., Iacobuzio-Donahue, C. A., Maitra, A., Parmigiani, G., Kern, S. E., Velculescu, V. E., Kinzler, K. W., Vogelstein, B., Eshleman, J. R., Goggins, M., Klein, A. P. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324: 217 only, 2009. [PubMed: 19264984] [Full Text: https://doi.org/10.1126/science.1171202]
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]
Orthwein, A., Noordermeer, S. M., Wilson, M. D., Landry, S., Enchev, R. I., Sherker, A., Munro, M., Pinder, J., Salsman, J., Dellaire, G., Xia, B., Peter, M., Durocher, D. A mechanism for the suppression of homologous recombination in G1 cells. Nature 528: 422-426, 2015. [PubMed: 26649820] [Full Text: https://doi.org/10.1038/nature16142]
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]
Rantakari, P., Nikkila, J., Jokela, H., Ola, R., Pylkas, K., Lagerbohm, H., Sainio, K., Poutanen, M., Winqvist, R. Inactivation of Palb2 gene leads to mesoderm differentiation defect and early embryonic lethality in mice. Hum. Molec. Genet. 19: 3021-3029, 2010. [PubMed: 20484223] [Full Text: https://doi.org/10.1093/hmg/ddq207]
Reid, S., Schindler, D., Hanenberg, H., Barker, K., Hanks, S., Kalb, R., Neveling, K., Kelly, P., Seal, S., Freund, M., Wurm, M., Batish, S. D., Lach, F. P., Yetgin, S., Neitzel, H., Ariffin, H., Tischkowitz, M., Mathew, C. G., Auerbach, A. D., Rahman, N. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nature Genet. 39: 162-164, 2007. [PubMed: 17200671] [Full Text: https://doi.org/10.1038/ng1947]
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]
Xia, B., Dorsman, J. C., Ameziane, N., de Vries, Y., Rooimans, M. A., Sheng, Q., Pals, G., Errami, A., Gluckman, E., Llera, J., Wang, W., Livingston, D. M., Joenje, H., de Winter, J. P. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nature Genet. 39: 159-161, 2007. [PubMed: 17200672] [Full Text: https://doi.org/10.1038/ng1942]
Xia, B., Sheng, Q., Nakanishi, K., Ohashi, A., Wu, J., Christ, N., Liu, X., Jasin, M., Couch, F. J., Livingston, D. M. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Molec. Cell 22: 719-729, 2006. [PubMed: 16793542] [Full Text: https://doi.org/10.1016/j.molcel.2006.05.022]
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]