title: Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry.
abstract: Loss-of-function mutations in PALB2 are associated with an increased risk of breast cancer, with recent data showing that female breast cancer risks for PALB2 mutation carriers are comparable in magnitude to those for BRCA2 mutation carriers. This study applied targeted massively parallel sequencing to characterize the mutation spectrum of PALB2 in probands attending breast cancer genetics clinics in the USA. The coding regions and proximal intron-exon junctions of PALB2 were screened in probands not known to carry a mutation in BRCA1 or BCRA2 from 1,250 families enrolled through familial cancer clinics by the Breast Cancer Family Registry. Mutation screening was performed using Hi-Plex, an amplicon-based targeted massively parallel sequencing platform. Screening of PALB2 was successful in 1,240/1,250 probands and identified nine women with protein-truncating mutations (three nonsense mutations and five frameshift mutations). Four of the 33 missense variants were predicted to be deleterious to protein function by in silico analysis using two different programs. Analysis of tumors from carriers of truncating mutations revealed that the majority were high histological grade, invasive ductal carcinomas. Young onset was apparent in most families, with 19 breast cancers under 50 years of age, including eight under the age of 40 years. Our data demonstrate the utility of Hi-Plex in the context of high-throughput testing for rare genetic mutations and provide additional timely information about the nature and prevalence of PALB2 mutations, to enhance risk assessment and risk management of women at high risk of cancer attending clinical genetic services.
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC, 3010, Australia, tun@unimelb.edu.au.
authors.forename: Tú
authors.initials: T
authors.lastname: Nguyen-Dumont
authors.forename: Fleur
authors.initials: F
authors.lastname: Hammet
authors.forename: Maryam
authors.initials: M
authors.lastname: Mahmoodi
authors.forename: Helen
authors.initials: H
authors.lastname: Tsimiklis
authors.forename: Zhi L
authors.initials: ZL
authors.lastname: Teo
authors.forename: Roger
authors.initials: R
authors.lastname: Li
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Pope
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Terry
authors.forename: Saundra S
authors.initials: SS
authors.lastname: Buys
authors.forename: Mary
authors.initials: M
authors.lastname: Daly
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Ingrid
authors.initials: I
authors.lastname: Winship
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Park
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001943:Breast Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D004252:DNA Mutational Analysis; D055088:Early Detection of Cancer; D005091:Exons; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D012042:Registries; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins