Hereditary cancer screening: Case reports and review of literature on ten Ashkenazi Jewish founder mutations

Abstract

Background: Historically, three founder mutations in the BRCA1/2 (OMIM 113705; OMIM 600185) genes have been the focus of cancer risks within the Ashkenazi Jewish (AJ) population. However, there are several additional mutations associated with increased susceptibility to cancer in individuals of AJ ancestry.

Methods: We report three patients who exemplify the need to keep these additional founder mutations in mind when pursuing hereditary cancer genetic testing of individuals in this population. All gene sequences in this paper were aligned to reference sequences based on human genome build GRCh37/UCSC hg19.

Results: review of the literature discusses that the combined risk is 12.36%-20.83% forhaving 1 of the 10 hereditary cancer AJ founder mutations in the BRCA1, BRCA2, CHEK2 (OMIM 604373), APC (OMIM 611731), MSH2 (OMIM 609309), MSH6 (OMIM 600678), and GREM1 (OMIM 603054) genes for individuals of AJ ancestry.

Conclusion: We recommend testing for all 10 of these AJ founder cancer susceptibility mutations for individuals within this population as standard screening in order to ensure appropriate cancer risk management and cascade testing.

Keywords: APC; BRCA1; BRCA2; CHEK2; GREM1; MSH2; MSH6; Ashkenazi; Jewish; breast cancer; cascade testing; colon cancer; founder mutations.

Figure 1

Pedigree of Patient 1. ¹Yr, ¹years; +², ²positive for pathogenic mutation

Figure 2

Pedigree of Patient 2. ¹Yr, ¹years; +², ²positive for pathogenic mutation

Figure 3

Pedigree of Patient 3. ¹Yr, ¹years; +², ²positive for pathogenic mutation; VUS³, ³variant of uncertain clinical significance