Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326 (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326 and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326 and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n 2233), as well as 52 tissues reported in the GTEx database. Results: The cancer risks associated with K3326 are fundamentally different from those associated with 999del5. We report for the first time an association between K3326 and small cell lung cancer (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.35 to 3.16) and squamous cell carcinoma of the skin (OR 1.69, 95% CI 1.26 to 2.26). Individuals homozygous for K3326 reach old age and have children. Unlike BRCA2 999del5, the K3326 allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. Conclusions: K3326 associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326 allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormoneresponsive tissues but may be less efficient in responding to genotoxic stress.,
National Cancer Institute. Journal (Print)

Rafnar, T., Sigurjonsdottir, G.R. (Gudbjorg R), Stacey, S., Halldorsson, G. (Gisli), Sulem, P., Pardo Cortes, L., … Zwart, J.-A. (2018). Association of brca2 k3326∗ with small cell lung cancer and squamous cell cancer of the skin. National Cancer Institute. Journal (Print), 110(9), 967–974. doi:10.1093/jnci/djy002