BRCA2

Overview

BRCA2 is a critical homologous recombination DNA repair factor. Germline and somatic BRCA2 mutations are among the most well-characterized cancer predisposition alterations, particularly for ovarian, breast, pancreatic, and prostate cancers. In the corpus, BRCA2 alterations appear across HGSOC precursors, endometrial carcinoma, anaplastic thyroid carcinoma, HCC, cervical cancer, and prostate cancer.

Alterations observed in the corpus

Germline BRCA2 mutations in 12 of 44 HGSOC patients in a multimodal spatial profiling study of fallopian tube precursor lesions; BRCA2 deletion in one paired sample was detected by cfDNA exclusive of tissue sequencing PMID:39386723.
BRCA2 deleted in 33.6% of anaplastic thyroid carcinoma (ATC), 13.6% of co-differentiated thyroid cancer (co-DTC), and 4.5% of papillary thyroid cancer (PTC); deletion associated with better survival in ATC (multi-omic landscape study, n=87 specimens) PMID:38412093.
BRCA2 alterations detected in 4% of advanced HCC patients by cfDNA profiling (MSK-ACCESS, 51 patients); combined BRCA1/2 in 8%; one sample showed cfDNA-exclusive BRCA2 alteration PMID:37769223.
Pathogenic somatic BRCA2 alterations in 2 of 3 cervical cancer patients with BRCA alterations in a 177-patient cervical cancer genomic landscape study PMID:37643132.
BRCA2/BRCA1 mutation rates elevated in MSI-H/dMMR (17.5%) and TMB-H/MSS (21%) vs. TMB-L/MSS (5.2%) prostate cancer; likely passenger events in the MSI/hypermutated context rather than primary actionable drivers PMID:38949888.
ATM, BRCA1, BRCA2, and CHEK2 — DDR pathway genes with driver genomic alterations predominantly in prostate adenocarcinoma PDXs (44 PDXs from 38 patients) PMID:38488813.
BRCA2 significantly over-expressed (FDR < 0.01, Welch’s t-test) in the undifferentiated nC3 cluster of high-risk neuroblastoma tumors in a single-nuclei transcriptomic study of 11 tumors; nC3 is enriched for MYCN-amplified and/or 11q-deleted genotypes PMID:34493726.
Pathogenic germline/somatic BRCA2 variants — along with other HRD-DDR gene alterations — used as the primary basis for HRD subtype assignment in a 444-patient HGSOC multimodal risk-stratification study; HRD status alone yielded only modest OS discrimination (concordance index 0.52) PMID:35764743.
BRCA2 alterations dose-dependently associated with NLP-derived Gleason score in PRAD in the MSK-CHORD real-world cohort (n=42,655 patients) PMID:39506116.
Germline pathogenic BRCA2 alterations in 3.7% of PAAD; strong selection for biallelic LOH in carriers; BRCA2 alterations associated with longer first-line OS (HR_adj = 0.66, P = 0.038); all 10 long-PARPi-responder BRCA2 tumors had biallelic inactivation in a 2,336-tumor PDAC genomic cohort PMID:39753968.
BRCA2 alterations in 2 cases (1%) in a cfDNA study of metastatic urothelial carcinoma (mUC, n=200); univariable signal of shorter OS (HR 6.06, 95% CI 1.45–25.3; p = 0.014) but n=2 limits inference; pooled into underpowered DDR analysis PMID:40256659.
Germline P/LP variants identified as incidental findings in KIT/PDGFRA-mutant GISTs; 4/4 BRCA2 variants in tumor-only sequencing were germline PMID:36593350
Mutated in 10% of a longitudinal African breast cancer cohort PMID:36585450
Germline/somatic mutations define HRD-Del subtype with interstitial deletions in HGSOC; 16/81 patients with HLA LOH in validation cohort PMID:36517593
BRCA2 screened as DDR candidate in FBXO7 synthetic lethality study; referenced for PARP inhibitor SL paradigm PMID:36334560
BRCA2 identified as a DNA damage repair gene with high prevalence of non-silent variants in metastatic UC PMID:36333289
BRCA2 oncogenic mutations in 6 GBC patients (OncoKB level 3B); associated with HRD and PARP inhibitor eligibility PMID:36228155
Found mutated in HGSOC tumors in TCGA integrated genomic analysis of ovarian carcinoma, contributing to homologous recombination deficiency PMID:21720365
Somatic mutations in 3/65 TNBC cases in a WGS breast cancer cohort; BRCA2 pathway linked to sporadic breast cancer via EMSY amplification PMID:22495314
Mutated in breast cancer (TCGA, 510 tumors); BRCA2 mutations identified across molecular subtypes, associated with homologous recombination deficiency PMID:23000897
Inactivating mutation contributing to G2/M checkpoint pathway alteration in transitional cell carcinoma (TCC) of the bladder PMID:24121792
Somatic mutation in 1/23 (4%) pancreatic acinar carcinomas; Fanconi-anemia-pathway member, candidate for DNA cross-linking agents and PARP inhibition PMID:24293293
HBOC gene included in the standard multigene panel for hereditary/familial gastric cancer risk stratification PMID:24816255
Truncating somatic mutation in one ERCC2-WT cisplatin responder in muscle-invasive urothelial carcinoma; absent in non-responders PMID:25096233
Mutations in ~3–5% of CCA; provides rationale for PARP inhibitors and platinum agents PMID:25526346
Mutated in 17/294 (5.8%) Tianjin gastric cancer cases and 28/289 TCGA STAD cases; independent predictor of longer survival in pooled cohort (HR 0.37, P=0.05); predominantly missense unlike breast/ovarian; one case carried BRCA2 p.E3002D/p.G602fs across separate tumor clones PMID:25583476
DNA double-strand-break and Fanconi-anaemia pathway lesion enriched in high-CNV PDA clusters; nominates olaparib (PARP inhibitor) and cross-linking agents (mitomycin-C) as therapeutic candidates PMID:25855536
Biallelic loss (somatic + germline) totaling 19.3% of mCRPC cases with BRCA1/ATM; multiple patients with germline BRCA2 + somatic second hit; some exhibited clinical responses to PARP inhibition PMID:26000489
High Cyclin E1, FoxM1, PCNA, pChk1-S345, Rad50, Rad51, XRCC1, and BRCA2 protein characterize the proliferative ILC transcriptional subtype, which is associated with worse disease-specific and overall survival in METABRIC PMID:26451490
Inactivation in 3% of primary prostate cancer (germline + somatic); all 6 germline mutations were K3326* (C-terminal truncation, debated pathogenicity); 2 tumors had focal homozygous deletions with low transcript; RB1 heterozygous loss often co-incident with BRCA2 loss at 13q PMID:26544944
Homozygous deletion shared across primary tumour, lymph-node metastasis, and CRPC-NE metastases in patient WCMC7520, marking a common clonal ancestor and supporting divergent clonal evolution model in metastatic prostate cancer PMID:26855148
BRCA2 included in the Fanconi anemia pathway gene set upregulated in high-cell-cycle-progression mCRPC tumors (linked to RB1 loss/E2F1 activation); homozygous deleterious BRCA2 events were used as part of the DNA-repair-defect classifier predicting longer carboplatin response (P = 0.02) PMID:26928463
Recurrent likely loss-of-function nsSNVs across NPM1-interacting, POLH-interacting, and FANCD2-interacting domains; enriched in anti-PD-1 responders (28% vs 6% non-responders; Fisher P=0.002, OR=6.2); BRCA2-mutant melanomas have higher overall mutational loads; proposed as candidate immunotherapy response biomarker PMID:26997480
Inactivating/germline mutations identified in breast cancer within the METABRIC 2,433-sample cohort; pathogenic germline classification performed in-cohort PMID:27161491
BRCA2 deletion flagged as actionable in cisplatin-resistant germ cell tumors; PARP inhibitor sensitivity implicated PMID:27646943
BRCA2 germline variants advance lung cancer onset by 12.2 years in young lung cancer; specific variant p.Arg2784Trp reported by Donner et al. PMID:27346245
BRCA2 among additional recurrently mutated genes in a 62-patient uRCC MSK-IMPACT cohort PMID:27713405
22Rv1 prostate cancer cell line carries monoallelic BRCA2 T3033Nfs*11 loss-of-function; BRCA2-WT rescue does not abolish olaparib + spautin-1 synergy, indicating the synthetic-lethal effect is independent of this BRCA2 background PMID:28068672
8 likely-inactivating truncating mutations (0.9%) in LUAD (MSK-IMPACT, n=860); level 2B actionability based on olaparib approval in BRCA-mutant ovarian carcinoma; no patient received matched PARP-inhibitor therapy PMID:28336552
Less frequent DDR alteration in high-grade non-muscle-invasive bladder cancer (NMIBC), contributing to the 30% DDR-altered fraction; DDR-altered tumors carry markedly elevated mutational burden supporting checkpoint immunotherapy PMID:28583311
BRCA2 enriched in Cluster 1 of cholangiocarcinoma (p < 0.05) PMID:28667006
BRCA2 is a recurrently altered candidate driver in medulloblastoma, stratified across subgroups; listed among candidates in WNT/SHH/Group 3/Group 4 oncoprint analysis PMID:28726821
BRCA2 germline PPGMs significantly enriched vs. ExAC in MET500 pan-cancer metastatic cohort (9 PPGM carriers); HR deficiency implies PARP inhibitor sensitivity PMID:28783718
BRCA2 somatic alterations are clonal/truncal in matched prostate tumor samples; 9% germline pathogenic in 221 tested patients; combined germline+somatic frequency drives PARP-inhibitor and platinum sensitivity rationale (olaparib, TOPARP-A) PMID:28825054
placeholder
Alterations in BRCA2 observed in 22% of MSI-H vs 1% of MSS mCRC tumors in a 1,122-patient panel sequencing cohort PMID:29316426.
Novel BRCA2 mutation finding in HPV(+) vulvar squamous cell carcinoma identified by whole-exome sequencing of 15 tumors PMID:29422544.
BRCA2 is confirmed as an established driver in prostate cancer with metastasis-vs-primary enrichment quantified across 1,013 prostate cancers (prad_p1000); frequent biallelic CDK12 inactivation in metastatic prostate cancer supports BRCA2 loss as a therapeutically relevant DNA-repair phenotype. PMID:29610475
BRCA2 was included in the 25-gene HBOC candidate panel screened via WES in a pediatric cancer predisposition cohort (n=372); no LP/PVs were detected in this cohort. PMID:29489754

Cancer types (linked)

OVT — Germline BRCA2 mutations in HGSOC; HRD via BRCA1/2 is the primary PARP inhibitor vulnerability PMID:39386723.
THPA — BRCA2 deletion in 33.6% of ATC; paradoxically associated with better ATC survival PMID:38412093.
HCC — BRCA2 detected by cfDNA in 4% of advanced HCC; actionable (OncoKB level) PMID:37769223.
CESC — Pathogenic somatic BRCA2 alterations in a subset of cervical cancers PMID:37643132.
PRAD — DDR gene alterations including BRCA2 in prostate cancer adenocarcinoma PDXs; elevated rates in MSI-H/dMMR prostate cancer as likely passengers PMID:38488813 PMID:38949888.
Neuroblastoma (NBL) — BRCA2 over-expression marks the high-risk undifferentiated nC3 cluster at single-nuclei resolution; significance confirmed at FDR < 0.01 PMID:34493726.

Co-occurrence and mutual exclusivity

In HGSOC, germline BRCA2 mutations define a subset with HRD; somatic events and epigenetic silencing contribute to additional cases PMID:39386723.
In MSI-H/dMMR prostate cancer, elevated BRCA2 mutation rates are attributed to the hypermutator context rather than functional HRD; PARP inhibitor responses were lower in this population PMID:38949888.

Therapeutic relevance

BRCA2 alterations are actionable across cancer types; PARP inhibitors and platinum are established strategies for HRD-associated malignancies PMID:37769223.
In ATC, BRCA2 deletions alongside ATM and BRCA1 alterations rationalize PARP inhibitor trials; the counterintuitive association of BRCA2 deletion with better ATC survival may reflect HRD-mediated mutational burden or immune stimulation PMID:38412093.
In MSI-H/dMMR prostate cancer, elevated BRCA1/2 mutation rates likely represent passenger events; lower PARP inhibitor responses than expected have been reported in this population PMID:38949888.

Open questions

The mechanistic basis for BRCA2 deletion being associated with better survival in ATC (vs. the typical adverse implications of HRD) is unexplained and requires functional investigation PMID:38412093.
Whether BRCA2 deletions in ATC confer platinum or PARP inhibitor sensitivity is not directly tested in the corpus PMID:38412093.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36593350

This page was processed by crosslinker on 2026-05-14. - PMID:36585450

This page was processed by crosslinker on 2026-05-14. - PMID:36517593

This page was processed by crosslinker on 2026-05-14. - PMID:36334560

This page was processed by crosslinker on 2026-05-14. - PMID:36333289

This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:21720365

This page was processed by crosslinker on 2026-05-14. - PMID:22495314

This page was processed by crosslinker on 2026-05-14. - PMID:23000897

This page was processed by crosslinker on 2026-05-14. - PMID:24121792

This page was processed by crosslinker on 2026-05-14. - PMID:24293293

This page was processed by crosslinker on 2026-05-14. - PMID:24816255

This page was processed by crosslinker on 2026-05-14. - PMID:25096233

This page was processed by crosslinker on 2026-05-14. - PMID:25526346

This page was processed by crosslinker on 2026-05-14. - PMID:25583476

This page was processed by crosslinker on 2026-05-14. - PMID:25855536

This page was processed by crosslinker on 2026-05-14. - PMID:26000489

This page was processed by crosslinker on 2026-05-14. - PMID:26451490

This page was processed by crosslinker on 2026-05-14. - PMID:26544944

This page was processed by crosslinker on 2026-05-14. - PMID:26855148

This page was processed by entity-page-writer on 2026-05-15. - PMID:26928463

This page was processed by entity-page-writer on 2026-05-15. - PMID:26997480

This page was processed by entity-page-writer on 2026-05-15. - PMID:27161491

This page was processed by entity-page-writer on 2026-05-15. - PMID:27646943

This page was processed by wiki-cli on 2026-05-14. - PMID:27346245

PMID:27713405

This page was processed by entity-page-writer on 2026-05-15. - PMID:28068672

This page was processed by wiki-cli on 2026-05-14.

This page was processed by entity-page-writer on 2026-05-15. - PMID:28336552

This page was processed by wiki-cli on 2026-05-14. - PMID:28583311

This page was processed by entity-page-writer on 2026-05-15. - PMID:28667006

This page was processed by wiki-cli on 2026-05-15. - PMID:28726821

This page was processed by wiki-cli on 2026-05-15. - PMID:28783718

This page was processed by wiki-cli on 2026-05-15. - PMID:28825054

This page was processed by wiki-cli on 2026-05-15. - PMID:29122777

This page was processed by wiki-cli on 2026-05-15. - PMID:29316426

This page was processed by wiki-cli on 2026-05-15. - PMID:29422544

This page was processed by wiki-cli on 2026-05-15. - PMID:29610475

This page was processed by wiki-cli on 2026-05-15. - PMID:29489754

This page was processed by wiki-cli on 2026-05-15.