PALB2 c.2257C>T truncating variant is a Greek founder and is associated with high breast cancer risk

J Hum Genet. 2019 Aug;64(8):767-773. doi: 10.1038/s10038-019-0612-6. Epub 2019 May 14.


PALB2 loss-of-function variants play an important role in breast, pancreatic and possibly, ovarian and gastric cancer susceptibility. Their frequency can be influenced by founder effects, already described in some populations. Herein, we have assessed the possible founder effect of PALB2 c.2257C>T (p.Arg753*) truncating variant among Greek breast cancer patients, while investigating possible correlations with cancer diagnoses. Following a lead deriving from a background study of highly selected Greek breast cancer patients, a total of 2496 breast and 697 ovarian cancer patients were directly genotyped for the PALB2 c.2257C>T truncating variant. Consequently, haplotype analysis was conducted on identified carriers, using seven microsatellite markers. The prevalence of the PALB2 variant was 0.24% (6/2496) and 0.14% (1/697) among breast and ovarian cases, respectively. Family history seems to be an important factor for the variant identification, although not reaching statistical significance. Microsatellite analysis on 12 carriers revealed a common shared haplotype, spanning a chromosomal region of ~1.2 Mb; the variant was possibly introduced in the Greek population ~1600 years ago. The variant confers high breast cancer risk, as illustrated by comparison with publicly available control groups. Genetic testing for PALB2, especially for the Greek founder c.2257C>T truncating variant, should be seriously considered in Greek breast cancer cases, since such findings could assist appropriate clinical management for the patients and their families.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles*
  • Amino Acid Substitution
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / epidemiology*
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • DNA Mutational Analysis
  • Fanconi Anemia Complementation Group N Protein / genetics*
  • Female
  • Founder Effect*
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • Germ-Line Mutation*
  • Greece / epidemiology
  • Haplotypes
  • Hereditary Breast and Ovarian Cancer Syndrome / diagnosis
  • Hereditary Breast and Ovarian Cancer Syndrome / epidemiology
  • Hereditary Breast and Ovarian Cancer Syndrome / genetics
  • Humans
  • Loss of Function Mutation
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Pedigree
  • Risk Assessment
  • Risk Factors
  • Sequence Deletion*
  • Young Adult


  • Fanconi Anemia Complementation Group N Protein
  • PALB2 protein, human