rs11571833

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This is a stop gained variant in the BRCA2 gene.

Key Literature Trait Associations

Lung cancer

rs11571833-T in BRCA2 confers substantially elevated lung cancer risk, with the strongest signal in the squamous cell carcinoma subtype. A large multi-stage GWAS (Wang et al. 2014, Nature Genetics; 21,594 cases and 54,156 controls combined) identified an OR of 2.47 for squamous cell lung cancer (p=4.74×10⁻²⁰) and OR 1.83 for all lung cancer (p=2×10⁻¹⁹), representing one of the largest genetic effect sizes documented for a common-exposure cancer. An independent replication study (Sang et al. 2022) confirmed the association (OR 2.18, p=0.006). The T allele frequency of ~1% in Europeans makes this a rare but high-impact variant. The mechanism likely involves impaired DNA repair in the bronchial epithelium exposed to carcinogens.

Wang Y et al. “Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer.” Nature Genetics 46(7):736-41 (2014)
Allele T
OR 2.47
p 4.7e-20
N 75,750
Large GWAS
European
“Rare germline deleterious variants increase susceptibility for lung cancer”
Allele T
OR 2.18
p 6.0e-3
N 2,777
Preliminary work
European

Breast Cancer Risk (Moderate Penetrance)

The BRCA2 K3326X variant (c.9976A>T, p.Lys3326Ter) creates a premature stop codon that truncates the final 93 amino acids of the BRCA2 protein. Unlike classic pathogenic BRCA2 mutations, this is a low-to-moderate risk allele: carrying one copy is associated with approximately 28% increased risk of breast cancer and 26% increased ovarian cancer risk. The truncated protein retains enough function to be compatible with health in most carriers. Present in ~0.7% of Europeans, clinical management recommendations differ from classic BRCA2 pathogenic variants.

Meeks HD et al. “BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.” Journal of the National Cancer Institute 108(2):djv315 (2016)
Allele T
OR 1.28
p 1.0e-8
Large GWAS
“Reevaluation of the BRCA2 Truncating Allele c.9976A>T (p.Lys3326Ter) in a Familial Breast Cancer Context”
Allele T
OR 1.53
p 4.7e-2
N 4,630
Preliminary work
Australian/European

Ovarian cancer

The BRCA2 K3326X variant (rs11571833-T) is associated with elevated invasive ovarian cancer risk, with OR 1.26 (95% CI 1.10–1.43, p=3.8×10⁻³) in the large iCOGS consortium study (Meeks et al. 2015). The association is stronger for high-grade serous ovarian cancer, the most lethal subtype. Importantly, among BRCA1 pathogenic variant carriers, K3326X showed a paradoxical inverse association (HR 0.43), suggesting possible competitive or epistatic interactions in the context of pre-existing DNA repair deficiency. The variant is most relevant in women of European ancestry where allele frequency reaches ~0.8%.

Meeks HD et al. “BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.” Journal of the National Cancer Institute 108(2):djv315 (2016)
Allele T
OR 1.26
p 3.8e-3
N 160,433
Preliminary work
multi-ancestry (predominantly European)

Pancreatic ductal adenocarcinoma

rs11571833-T in BRCA2 is associated with elevated risk of sporadic pancreatic ductal adenocarcinoma (PDAC), with OR 1.78 (95% CI 1.26–2.52, p=1.19×10⁻³) in a European case-control study of 2,935 cases and 5,626 controls (Obazee et al. 2019). This association holds for sporadic PDAC independent of family history, suggesting K3326X contributes to pancreatic cancer risk through partial loss of BRCA2's DNA repair function. Given PDAC's dismal prognosis, even modest genetic risk factors may have clinical utility in identifying candidates for enhanced surveillance. The association has not yet been validated in large multi-ethnic cohorts.

“Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma”
Allele T
OR 1.78
p 1.2e-3
N 8,561
Preliminary work
European

Bladder cancer

A meta-analysis of GWAS data (Ge et al. 2016) found that rs11571833-T is associated with increased urinary tract cancer risk, with the strongest signal for bladder cancer specifically (OR 1.60, p=0.010) and overall urinary tract cancer (OR 1.45, p=0.013). The study pooled existing GWAS datasets and applied logistic regression meta-analytic methods. Evidence is currently limited to this single meta-analysis, and validation in an independent large-scale cohort is needed before this association can be considered established. Given the biological plausibility of impaired BRCA2-mediated DNA repair in urothelial carcinogenesis, further replication is warranted.

Ge Y et al. “Rare variants in BRCA2 and CHEK2 are associated with the risk of urinary tract cancers.” Scientific Reports (2016)
Allele T
OR 1.60
p 1.0e-2
Candidate gene study
European
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GWAS Catalog Trait Associations (10)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

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ClinVar annotation

Pathogenic★★★★
50 submitters31 publications

BRCA2-related cancer predisposition; Breast and/or ovarian cancer; Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2); Familial cancer of breast; Fanconi anemia complementation group D1; Hereditary breast ovarian cancer syndrome; Hereditary cancer-predisposing syndrome; Malignant tumor of breast; not specified

View on ClinVar →
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Research that mentions this SNP (1)

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Capillary Electrophoresis Analysis of Conventional Splicing Assays: IARC Analytical and Clinical Classification of 31BRCA2Genetic Variants
FunctionalN=1,279Gorka Ruiz de Garibay et al.(2014)· Human Mutation

This paper performs capillary electrophoresis analysis of splicing assays on 31 BRCA2 genetic variants to analytically classify them according to IARC guidelines. Three clinically relevant Class-5 variants were identified (c.682-2A>G, c.7617+1G>A, c.8954-5A>G), 27 variants were classified as Class-2 (non-splicing altering), and rs9534262 (c.7806-14T>C) was identified as a splicing quantitative trait locus (sQTL) that regulates BRCA2 alternative splicing (p=0.006).

Traits studied:BRCA2 splicing alterationsBreast cancerHereditary breast and ovarian cancer (HBOC)Ovarian cancer
PubMedDOIMetascience Observatory

Gene information from NCBI Gene. Variant classifications from ClinVar.

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