ABSTRACT
BACKGROUND: The role of deep intronic variants in hereditary cancer susceptibility has been largely understudied. Previously, the BRCA2 c.6937 + 594T>G variant has been shown to preferentially promote the inclusion of a 95 nucleotide cryptic exon and to introduce a premature termination codon. Our objective was to further assess the pathogenicity of the BRCA2 c.6937 + 594T>G deep intronic variant. PATIENTS AND METHODS: We examined the association between BRCA2 c.6937 + 594T>G and breast cancer (BC) risk in 464 BC cases and 497 noncancer controls from Puerto Rico. RESULTS: The overall frequency of the G allele was 2.1% in this population. There was no association between the TG/GG genotypes and BC risk in the uncorrected model and after correcting for confounders. There was only one carrier of the GG genotype. This individual did not have personal or family history of cancer and did not meet the National Comprehensive Cancer Network criteria for hereditary cancer genetic testing. CONCLUSIONS: Although previous work has demonstrated that the BRCA2 c.6937 + 594T>G variant affects splicing, this association study does not support a pathogenic role for the BRCA2 c.6937 + 594T>G intronic variant in breast and ovarian cancer syndrome susceptibility. Furthermore, it emphasizes the need to take into account multiple diverse populations in association studies for the assessment of variant pathogenicity.