PALB2 (Partner and localizer of BRCA2) Gene Mutation Analysis

Fanconi Anemia Complementation Group N
Pancreatic Cancer Susceptibility
Breast Cancer Susceptibility

Partner and localizer of BRCA2 (PALB2, OMIM *610355) was originally identified as a BRCA2-interacting protein that is crucial in physically and functionally connecting BRCA1 and BRCA2 to form a “BRCA complex”.1 The integrity of the “BRCA complex” is essential for the maintenance of genomic stability via recombinational repair and the avoidance of cancer and Fanconi anemia (FA). Germline monoallelic (heterozygous) mutations in PALB2 are associated with increased risk of breast and pancreatic cancer,whereas biallelic mutations in PALB2 lead to FA.1,3,4,10 The PALB2 gene consists of 13 exons and maps to chromosome 16p12.2.

Fanconi anemia is a recessive chromosomal instability syndrome with both autosomal and X-linked inheritance that currently includes 13 subtypes. Biallelic mutations in PALB2 gene lead to Fanconi anemia subtype N.5 The phenotypes associated with biallelic BRCA2 and PALB2 mutations are markedly similar to each other. PALB2-related FA have a typical FA phenotype with growth retardation and variable congenital malformations. Furthermore, PALB2-related FA phenotype is associated with an unusually severe predisposition to childhood solid tumors.

PALB2 gene has been recently identified as the second most important susceptibility gene for familial pancreatic cancer (FPC) right after BRCA2.10 Jones et al. identified 3 (3.1%) truncating mutations in PALB2 in 96 American familial pancreatic cancer patients10. Each of these mutations produced a different stop codon. Some FPC patients with the PALB2 mutation had an associated history of breast cancer but not all. In another recent European study, Slater et al. found truncating mutations in 3 out of 81 (3.7%) European pancreatic cancer families, which all included breast cancers.2

PALB2 is also a breast cancer susceptibility gene. Rare germline monoallelic mutations in PALB2 present a relative risk of breast cancer of 2 to 4-times.4,6,8 Number of monoallelic PALB2 truncating mutations and a novel PALB2 gene deletion were identified in women with a strong family history of breast cancer and negative mutations in BRCA1 and BRCA2.1,8,9 There are also several founder PALB2 mutations reported in the literature. A French Canadian founder mutation 2323C>T has been reported in 2/356 (0.5%) unselected patients with early-onset breast cancer 7.PALB2 mutations have now been found in patients in many countries with frequencies varying from 0.6 to 2.7% in familial breast cancer cases.3 The average penetrance PALB2 mutations is not known at the moment.

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PALB2 Gene Mutation Analysis Assay Summary
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  1. Xia B et al.. Mol Cel. 2006; 22:719–29.
  2. Slater EP et al. Clin Genet. 201078(5):490-4.
  3. Tischkowitz M et al. Cancer Res. 2010;70(19):7353-9.
  4. Xia B et al. Nat Genet. 2007;39:159–61.
  5. Moldovan GL et al. Annu Rev Genet.2009;43:223–49.
  6. Byrnes GB et al. Breast Cancer Res. 2008;10:208.
  7. Foulkes WD et al. Breast Cancer Res. 2007;9:R83.
  8. Rahman N, Nat Gene. 2007;39:165–7.
  9. Dansonka-Mieszkowska A et al. BMC Med Genet. 2010; 11:20
  10. Jones S et al. Science. 2009;324 (5924):217.