title: Analysis of PALB2 in a cohort of Italian breast cancer patients: identification of a novel PALB2 truncating mutation.
abstract: PALB2 gene is mutated in about 1-2% of familial breast cancer as well as in 3-4% of familial pancreatic cancer cases. Few studies have reported mutations in Italian patients with breast or pancreatic cancer. We evaluate the occurrence of PALB2 mutations in Italian patients affected with hereditary breast and ovarian cancers and define the pathological significance of the putative allelic variants. We recruited 98 patients (F = 93, M = 5) affected with breast and/or ovarian cancer, negative for mutations in BRCA1 and BRCA2 (BRCAX). Genomic DNA was isolated from peripheral blood lymphocytes, PALB2 coding regions and adjacent intronic were sequenced; in silico predictions were carried out using prediction programs. Mutational analysis of PALB2 gene revealed the novel mutation c.1919C>A (p.S640X) in a 29 years old woman with breast cancer. The c.1919C>A (p.S640X) mutation causes the lack of C-terminus region inducing alteration of MORF4L1-PALB2 association and the lack of interaction of PALB2 with RAD51 and BRCA2. In addition, we identified two novel PALB2 variants, c.3047T>C (p.F1016S) and c.*146A>G. In silico analysis conducted for c.*146A>G indicates that this variant does not affect the splicing while c.3047T>C (p.F1016S) was predicted as damaging in three classifier algorithms. The proband carrier of c.3047T>C (p.F1016S) showed two breast cancer cases, two ovarian cancer cases and one pancreatic cancer in mother's family. c.3047T>C (p.F1016S) and c.*146A>G should be considered PALB2 UVs even though the genotype-phenotype correlation for these variants remains still unclear. Our findings indicate that the presence of PALB2 mutation should be routinely investigated in hereditary breast and ovarian cancers families since it could be of clinical relevance for clinical management.
authors: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via Luigi De Crecchio, 7, 80138, Naples, Italy, mariateresa.vietri@unina2.it.
authors: Maria Teresa
authors: MT
authors: Vietri
authors: Gemma
authors: G
authors: Caliendo
authors: Concetta
authors: C
authors: Schiano
authors: Amelia
authors: A
authors: Casamassimi
authors: Anna Maria
authors: AM
authors: Molinari
authors: Claudio
authors: C
authors: Napoli
authors: Michele
authors: M
authors: Cioffi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics; D018389:Codon, Nonsense; D015331:Cohort Studies; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D010375:Pedigree; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D018389:Codon, Nonsense; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins