Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center

Cancer. 2019 Mar 1;125(5):690-697. doi: 10.1002/cncr.31856. Epub 2018 Nov 27.

Abstract

Background: Genetic assessment in Ashkenazi Jewish (AJ) patients often is limited to BRCA1/2 founder mutation testing. With access to time-efficient and cost-efficient multigene panel testing, some advocate expanding genetic testing in this population. However, to the best of the authors' knowledge, rates of nonfounder BRCA1/2 mutations and mutations in cancer-associated genes other than BRCA1/2 among AJ are not known. In the current study, the authors sought to assess the prevalence of mutations other than BRCA1/2 founder mutations among AJ patients undergoing genetic assessment.

Methods: The authors reviewed the medical records for all AJ patients who underwent genetic assessment at a single institution between June 2013 and December 2016. Mutations were categorized as 1) BRCA1/2 AJ founder mutations (BRCA1 185delAG, BRCA1 5382insC, or BRCA2 6174delT); 2) nonfounder BRCA1/2 mutations; or 3) mutations in non-BRCA1/2 cancer-associated genes.

Results: A total of 732 AJ patients underwent genetic assessment. Of these, 371 patients (51%) had a personal history of breast or ovarian cancer, 540 patients (73.8%) had a family history of breast cancer, and 132 patients (18%) had a family history of ovarian cancer. In the study population, 101 patients (13.8%) were found to have a pathogenic mutation, 78 patients (10.7%) had a BRCA1/2 founder mutation, 3 patients (0.4%) had a nonfounder BRCA1/2 mutation, and 20 patients (2.7%) had a mutation in a non-BRCA1/2 cancer-associated gene. Non-BRCA1/2 cancer-associated genes harboring mutations included RAD51D, TP53, mutS homolog 6 (MSH6), checkpoint kinase 2 (CHEK2), adenomatous polyposis coli (APC), and Fanconi anemia group C protein (FANCC).

Conclusions: Among AJ patients found to have a pathogenic mutation on genetic assessment, approximately 22.8% had a mutation that would be missed with BRCA1/2 AJ founder mutation testing. Comprehensive multigene panel sequencing can provide clinically relevant genetic information for AJ patients and should be considered for genetic assessment in this population.

Keywords: BRCA1; BRCA2; Ashkenazi Jewish; Ashkenazi Jewish founder mutation testing; multigene panel.

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Checkpoint Kinase 2 / genetics
  • DNA-Binding Proteins / genetics
  • Fanconi Anemia Complementation Group C Protein / genetics
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Testing / methods*
  • Hereditary Breast and Ovarian Cancer Syndrome / genetics*
  • Humans
  • Jews / genetics*
  • Middle Aged
  • Prevalence
  • Sequence Analysis, DNA / methods*
  • Tumor Suppressor Protein p53 / genetics
  • Young Adult

Substances

  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • DNA-Binding Proteins
  • FANCC protein, human
  • Fanconi Anemia Complementation Group C Protein
  • G-T mismatch-binding protein
  • RAD51D protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Checkpoint Kinase 2
  • CHEK2 protein, human