K3326X and Other C-Terminal BRCA2 Variants Implicated in Hereditary Cancer Syndromes: A Review

Simple Summary The cancer associated protein BRCA2 is the subject of intense continual study. Because of this, new insights into the relation of specific variants of this gene and cancer are regularly generated. These discoveries shed light on cancer risk and management for patients carrying these mutations. Additionally, new techniques for variant discovery and investigation are developed and tested, further enhancing scientific and clinical understanding of this key protein. In this review we will investigate the recent literature associated with variants in the C-terminus of BRCA2 and their effect on health and cancer predisposition. Whole genome analysis and the search for mutations in germline and tumor DNAs is becoming a major tool in the evaluation of risk as well as the management of hereditary cancer syndromes. Because of the identification of cancer predisposition gene panels, thousands of such variants have been catalogued yet many remain unclassified, presenting a clinical challenge for the management of hereditary cancer syndromes. Although algorithms exist to estimate the likelihood of a variant being deleterious, these tools are rarely used for clinical decision-making. Here, we review the progress in classifying K3326X, a rare truncating variant on the C-terminus of BRCA2 and review recent literature on other novel single nucleotide polymorphisms, SNPs, on the C-terminus of the protein, defined in this review as the portion after the final BRC repeat (amino acids 2058-3418).