rs11571833 — BRCA2 K3326X

BRCA2 K3326X — A Moderate-Penetrance Stop Codon, Not a Pathogenic BRCA Mutation

BRCA2 is one of the most important DNA repair genes in the human genome, encoding a 3,418-amino acid protein that orchestrates homologous recombination¹¹ homologous recombination
The high-fidelity DNA repair pathway that uses a sister chromatid as a template to accurately repair double-strand breaks; BRCA2's primary role is loading RAD51 onto single-stranded DNA at break sites repair of double-strand DNA breaks. Pathogenic mutations that severely disrupt BRCA2 function carry lifetime breast cancer risks of 45-70% and ovarian cancer risks of 10-20%. The K3326X variant is fundamentally different: it creates a premature stop codon that truncates only the last 93 amino acids of the protein, leaving the core DNA repair domains intact. This distinction matters enormously for how carriers should understand their results.

The Mechanism

The c.9976A>T substitution converts lysine at position 3326 to a stop codon, truncating the final 93 residues of BRCA2. This C-terminal region contains the last four residues of a RAD51 binding domain²² RAD51 binding domain
RAD51 is the recombinase enzyme that BRCA2 loads onto single-stranded DNA at double-strand break sites; the C-terminal binding site is one of multiple RAD51 interaction interfaces on BRCA2, a nuclear localization signal, and a phosphorylation site at Thr3387³³ Thr3387
A threonine residue phosphorylated by CDK2; its loss may subtly alter cell cycle-dependent regulation of BRCA2 nuclear import. Critically, the eight central BRC repeats⁴⁴ BRC repeats
The primary RAD51-binding motifs (BRC1-BRC8) spanning residues 1002-2085, which are the main functional interface for loading RAD51 onto damaged DNA, the DNA binding domain, and the tower domain⁵⁵ tower domain
A helical structure within the DNA binding domain that directly contacts double-stranded DNA are all preserved.

The truncated protein is expressed at normal transcript levels and retains substantial homologous recombination activity. This explains why K3326X does not behave like classic pathogenic BRCA2 mutations: the protein is partially functional, not absent. The residual impairment appears to reduce repair efficiency enough to measurably increase cancer risk — particularly for cancers driven by environmental genotoxic exposures — without the catastrophic loss of function seen in frameshift or early truncation mutations.

The Evidence

The definitive epidemiological study came from the iCOGS consortium⁶⁶ iCOGS consortium
Meeks HD et al. BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers. JNCI, 2015, analyzing 76,637 cancer cases and 83,796 controls. K3326X carriers showed an OR of 1.28 (95% CI: 1.17-1.40) for breast cancer overall, rising to 1.46 for estrogen receptor-negative breast cancer and 1.50 for triple-negative breast cancer. Ovarian cancer risk was elevated at OR 1.26 (95% CI: 1.10-1.43), strongest for the serous subtype. Prostate cancer showed no significant association. Importantly, these associations were independent of other pathogenic BRCA2 variants.

For lung cancer, Wang et al.⁷⁷ Wang et al.
Wang Y et al. Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nature Genetics, 2014 identified K3326X as one of the strongest rare-variant associations in lung cancer genetics: OR 2.47 (P = 4.74 x 10^-20) for squamous cell lung cancer in a study of 21,594 cases and 54,156 controls. A subsequent Icelandic/Dutch study⁸⁸ Icelandic/Dutch study
Rafnar T et al. Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin. JNCI, 2018 extended this to small cell lung cancer (OR 2.06) and squamous cell skin cancer (OR 1.69), noting that K3326X associates primarily with cancers driven by environmental genotoxic exposures.

Martin et al.⁹⁹ Martin et al.
Martin ST et al. Increased prevalence of the BRCA2 polymorphic stop codon K3326X among individuals with familial pancreatic cancer. Oncogene, 2005 first flagged K3326X as functionally relevant, finding it in 5.6% of familial pancreatic cancer patients versus 1.2% of controls (OR 4.84). A comprehensive review¹⁰¹⁰ comprehensive review
Baughan S and Tainsky MA. K3326X and Other C-Terminal BRCA2 Variants Implicated in Hereditary Cancer Syndromes: A Review. Cancers, 2021 synthesized these findings, concluding that K3326X confers moderate risk increases across multiple cancer types, particularly those with strong environmental genotoxic components.

Practical Implications

K3326X carriers should understand two critical points. First, this is NOT a pathogenic BRCA2 mutation. It does not qualify for BRCA clinical management pathways such as prophylactic mastectomy or oophorectomy, risk-reducing salpingectomy, or PARP inhibitor eligibility. The moderate risk elevations (OR 1.2-1.5 for breast and ovarian cancer) are in a fundamentally different category from pathogenic BRCA2 mutations (lifetime risks of 45-70% for breast cancer).

Second, the risk pattern is real and actionable at the screening level. Enhanced breast cancer surveillance with supplemental imaging (breast MRI in addition to mammography) is a proportionate response for female carriers, particularly given the stronger association with ER-negative and triple-negative subtypes that mammography detects less reliably. For lung cancer, the substantially elevated risk (OR 2.47 for squamous cell) makes low-dose CT screening worth discussing with a physician, especially for carriers with any smoking history.

Interactions

K3326X sits in the broader context of DNA repair and cancer susceptibility. Carriers who also carry variants in other DNA repair pathway genes — such as ATM (rs1801516), CHEK2, or TP53 (rs1042522) — may have compounded impairment of genomic integrity maintenance. The Wang et al. 2014 study notably identified CHEK2 I157T (rs17879961) alongside K3326X as a large-effect lung cancer variant, suggesting these DNA damage checkpoint and repair pathways interact in determining cancer susceptibility. However, formal gene-gene interaction studies for K3326X combinations remain limited, and compound action recommendations should await stronger evidence.