New Perspectives on the Recurrent Monoallelic Germline Mutations of DNA Repair and Checkpoint Genes and Clinical Variability

Genet Test Mol Biomarkers. 2022 Jan;26(1):17-25. doi: 10.1089/gtmb.2021.0108.


Background: Inherited cancers account for ∼10% of cancer cases. Many hereditary cancers are associated with mutations in DNA repair and checkpoint genes making their clinical surveillance important. Methods: We screened 900 patients using a comprehensive cancer gene panel with the following diagnoses: familial (n = 537, 59.6%), colorectal (n = 117, 13%), breast-ovarian (n = 215, 23.8%), endometrium (n = 12, 1.3%), gastric (n = 11, 1.2%), and thyroid (n = 8, 0.8%). Results: The most commonly mutated genes identified were ATM, MSH6, MUTYH, CHEK2, APC, MLH1, RAD50, PALB2, MSH2, CDH1, and PMS2. The most prevalent heterozygous was MUTYH: c.884C>T(P295L), which was predominant in the breast-ovarian group. Notably, the MUTYH, MSH6, and MSH2 variants showed a higher incidence of extracolonic malignancy. Among the DNA mismatch repair (MMR) genes, MSH6 mutations were the most common, followed by mutations in MLH1, MSH2, PMS2, and EPCAM. Conclusion: These findings offer a new perspective and suggest that, beyond ATM, CHEK2, and PALB2, patients with germline monoallelic mutations in MUTYH, MSH6, APC, CDH1, MHS2, and PMS2 may present with a hereditary breast-ovarian cancer phenotype. Continued developments in assessing and researching new variants of known cancer candidate genes will play an important role in improving individual risk prediction, therapy, and prognosis for familial cancers.

Keywords: MUTYH; checkpoint; familial cancer; mismatch repair.

MeSH terms

  • Breast Neoplasms* / genetics
  • DNA Mismatch Repair / genetics
  • DNA-Binding Proteins / genetics
  • Female
  • Germ Cells
  • Germ-Line Mutation* / genetics
  • Humans


  • DNA-Binding Proteins