Concurrent Pathogenic Variants of BRCA1, MUTYH and CHEK2 in a Hereditary Cancer Family

Cancer Genet. 2022 Nov;268-269:128-136. doi: 10.1016/j.cancergen.2022.10.144. Epub 2022 Nov 1.


Concurrent pathogenic variants (PVs) in cancer predisposition genes have been reported in 0.1-2% of hereditary cancer (HC) patients. Determining concurrent PVs is crucial for the diagnosis, treatment, and risk assessment of unaffected family members. Next generation sequencing based diagnostic tests, which are widely used in HCs, enable the evaluation of multiple genes in parallel. We have screened the family members of a patient with bilateral breast cancer who was found to have concurrent PVs in BRCA1 (NM_007294.3;c.5102_5103del, p.Leu1701Glnfs*14) and MUTYH (NM_001128425.1;c.884C>T, p.Pro295Leu). Further analysis revealed concurrent PVs in CHEK2 (NM_007194.4;c.1427C>T, p.Thr476Met) and MUTYH (NM_001128425.1;c.884C>T, p.Pro295Leu) in the maternal uncle of the index case. Eight additional family members were found to have PVs in BRCA1 and MUTYH among 26 tested relatives. The sister and the brother of the index case who were diagnosed with breast and colon cancers, respectively, presented with the same genotype as the index case. Each family member was evaluated individually for clinical care and surveillance. This is the first report describing a family with BRCA1, MUTYH and CHEK2 concurrent PVs. Our findings provide valuable information for the assessment and management considerations for families with concurrent PVs.

Keywords: BRCA1; CHEK2; Concurrent variants; Hereditary cancer; MUTYH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA1 Protein / genetics
  • Breast Neoplasms* / pathology
  • Checkpoint Kinase 2 / genetics
  • Family
  • Female
  • Genetic Predisposition to Disease*
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans


  • BRCA1 Protein
  • BRCA1 protein, human
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • mutY adenine glycosylase