MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer

Genet Med. 2018 Oct;20(10):1167-1174. doi: 10.1038/gim.2017.254. Epub 2018 Jan 18.


Purpose: An association of Lynch syndrome (LS) with breast cancer has been long suspected; however, there have been insufficient data to address this question for each of the LS genes individually.

Methods: We conducted a retrospective review of personal and family history in 423 women with pathogenic or likely pathogenic germ-line variants in MLH1 (N = 65), MSH2 (N = 94), MSH6 (N = 140), or PMS2 (N = 124) identified via clinical multigene hereditary cancer testing. Standard incidence ratios (SIRs) of breast cancer were calculated by comparing breast cancer frequencies in our study population with those in the general population (Surveillance, Epidemiology, and End Results 18 data).

Results: When evaluating by gene, the age-standardized breast cancer risks for MSH6 (SIR = 2.11; 95% confidence interval (CI), 1.56-2.86) and PMS2 (SIR = 2.92; 95% CI, 2.17-3.92) were associated with a statistically significant risk for breast cancer whereas no association was observed for MLH1 (SIR = 0.87; 95% CI, 0.42-1.83) or MSH2 (SIR = 1.22; 95% CI, 0.72-2.06).

Conclusion: Our data demonstrate that two LS genes, MSH6 and PMS2, are associated with an increased risk for breast cancer and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.

Keywords: Lynch syndrome; MSH6; PMS2; breast cancer; mismatch repair.

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms / complications
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / complications
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA-Binding Proteins / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Germ-Line Mutation / genetics
  • Humans
  • Medical History Taking
  • Middle Aged
  • Mismatch Repair Endonuclease PMS2 / genetics*
  • MutL Protein Homolog 1 / genetics
  • MutS Homolog 2 Protein / genetics
  • Retrospective Studies
  • Risk Factors


  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • PMS2 protein, human
  • MSH2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein