BRCA2

Summary

BRCA2 (BRCA2 DNA repair associated, HGNC:1101) is a protein-coding gene on chromosome 13q13.1, encoding Breast cancer type 2 susceptibility protein (P51587). Involved in double-strand break repair and/or homologous recombination. In precision oncology, BRCA2 Mutation confers sensitivity to Rucaparib in Ovarian Cancer (CIViC Level A); 50 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 52.8% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

The product of this gene in involved in maintenance of genome stability. It is involved in double-strand break repair pathways during mitotic and meiotic homologous recombination and functions in protecting DNA replication forks. The encoded protein contains sites for interactions with PALB2 and EMSY and an N-terminal DNA binding domain. It also contains a RAD51 binding domain with multiple components. It has multiple BRC repeats, an alpha helix domain, oligonucleotide binding folds, and a tower-like domain. It has a nuclear localization signal and a phosphorylation site for cyclin-dependent kinase. The C-terminus of the protein can bind single-stranded and double-stranded DNA. The product of this gene interacts with multiple proteins, including RAD51. It is involved in recruiting RAD51 filaments to DNA double-strand break sites and also in cytoplasmic division. It also acts as a tumor suppressor. Mutations in this gene or decreased expression have been implicated in multiple tumor types, including breast, ovarian, pancreatic, prostate and other cancers.

Source: NCBI Gene 675 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fanconi anemia complementation group D1 (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 21
• Clinical variants (ClinVar): 21,654 total — 5115 pathogenic, 408 likely-pathogenic
• Phenotypes (HPO): 217
• Precision-oncology evidence (CIViC): 51 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 14 cancer types
• Cancer dependency (DepMap): dependent in 52.8% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000059

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1101
Approved symbol	BRCA2
Name	BRCA2 DNA repair associated
Location	13q13.1
Locus type	gene with protein product
Status	Approved
Aliases	FAD, FAD1, BRCC2, XRCC11
Ensembl gene	ENSG00000139618
Ensembl biotype	protein_coding
OMIM	600185
Entrez	675

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 8 nonsense_mediated_decay, 7 protein_coding, 4 retained_intron

ENST00000380152, ENST00000470094, ENST00000528762, ENST00000530893, ENST00000533776, ENST00000544455, ENST00000614259, ENST00000665585, ENST00000666593, ENST00000680887, ENST00000700199, ENST00000700200, ENST00000700201, ENST00000700202, ENST00000700203, ENST00000713677, ENST00000713678, ENST00000713679, ENST00000713680

RefSeq mRNA: 6 — MANE Select: NM_000059 NM_000059, NM_001406719, NM_001406720, NM_001406721, NM_001406722, NM_001432077

CCDS: CCDS9344

Canonical transcript exons

ENST00000380152 — 27 exons

Exon	Start	End
ENSE00000939167	32332272	32333387
ENSE00000939168	32336265	32341196
ENSE00000939169	32344558	32344653
ENSE00000939171	32346827	32346896
ENSE00000939173	32354861	32355288
ENSE00000939174	32356428	32356609
ENSE00000939175	32357742	32357929
ENSE00000939177	32363179	32363533
ENSE00000939178	32370402	32370557
ENSE00000939180	32370956	32371100
ENSE00000939183	32379317	32379515
ENSE00000939185	32379750	32379913
ENSE00000939187	32380007	32380145
ENSE00000939189	32394689	32394933
ENSE00001394102	32362523	32362693
ENSE00001484009	32316422	32316527
ENSE00003461148	32376670	32376791
ENSE00003560258	32396898	32397044
ENSE00003659301	32325076	32325184
ENSE00003666217	32319077	32319325
ENSE00003714754	32329443	32329492
ENSE00003717596	32398162	32400268
ENSE00003731761	32330919	32331030
ENSE00003739878	32326101	32326150
ENSE00003747332	32326242	32326282
ENSE00003749714	32326499	32326613
ENSE00004011581	32315508	32315667

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 94.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.2478 / max 296.1040, expressed in 1626 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134699	9.5194	1446
134700	1.8734	804
206998	0.6209	315
134698	0.4570	160
134701	0.3268	199
134702	0.2264	112
134703	0.2238	68

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.30	gold quality
secondary oocyte	CL:0000655	88.42	gold quality
ventricular zone	UBERON:0003053	84.77	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.70	gold quality
ganglionic eminence	UBERON:0004023	80.61	gold quality
oocyte	CL:0000023	78.93	gold quality
granulocyte	CL:0000094	76.11	gold quality
bone marrow cell	CL:0002092	75.12	gold quality
bone marrow	UBERON:0002371	74.05	gold quality
embryo	UBERON:0000922	73.93	gold quality
trabecular bone tissue	UBERON:0002483	73.41	gold quality
stromal cell of endometrium	CL:0002255	72.55	gold quality
calcaneal tendon	UBERON:0003701	71.64	gold quality
testis	UBERON:0000473	71.35	gold quality
colonic epithelium	UBERON:0000397	70.49	gold quality
left testis	UBERON:0004533	69.39	gold quality
right testis	UBERON:0004534	69.28	gold quality
leukocyte	CL:0000738	68.83	gold quality
monocyte	CL:0000576	68.79	gold quality
mononuclear cell	CL:0000842	68.44	gold quality
rectum	UBERON:0001052	68.44	gold quality
adrenal tissue	UBERON:0018303	68.33	gold quality
lymph node	UBERON:0000029	66.86	gold quality
buccal mucosa cell	CL:0002336	66.16	gold quality
cortical plate	UBERON:0005343	65.28	gold quality
spleen	UBERON:0002106	65.25	gold quality
vermiform appendix	UBERON:0001154	64.89	gold quality
esophagus mucosa	UBERON:0002469	63.64	gold quality
gall bladder	UBERON:0002110	62.89	gold quality
right coronary artery	UBERON:0001625	62.80	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-124858	yes	186.43
E-ANND-3	yes	7.19
E-CURD-119	no	209.38

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

4 targets.

Target	Regulation
DMC1	Unknown
PSMD3	Unknown
PSMD6	Unknown
RAD51	Unknown

Upstream regulators (CollecTRI, top): BRCA1, CTBP1, ELF1, ESR1, ESR2, ESRRB, FOXM1, HDAC1, HMG20B, KDM5B, MYC, MYOD1, NFKB1, NFKB, PARP1, RELA, SNAI2, TP53, USF1, USF2

miRNA regulators (miRDB)

32 targeting BRCA2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-548L	99.06	70.90	2560
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-548AO-5P	98.55	69.57	1362
HSA-MIR-548AX	98.55	69.58	1362
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-628-5P	98.36	67.74	844
HSA-MIR-147A	98.33	66.40	795
HSA-MIR-6500-3P	97.42	67.20	867
HSA-MIR-4793-5P	96.88	65.90	872

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 52.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Suppression of tumorigenicity of rat liver tumor cells by human chromosome 13: evidence against the involvement of pRb and BRCA2 (PMID:11788883)
• BRCA1 and BRCA2 mutations in Russian familial breast cancer (PMID:11793480)
• Germline mutation in BRCA2 associated with hypersensitivity to radiation (PMID:11807777)
• A low frequency of recurrent BRCA2 mutations has been found in breast and ovarian cancers in Spain. (PMID:11857748)
• Three Chinese cases carrying the recurrent BRCA2 mutation 3337C>T show sharing of some alleles, suggesting some degree of shared ancestry but not sufficient to demonstrate founder effect. (PMID:11857749)
• minor role of exon 1 among Sudanesse breast cancer patients (PMID:11883440)
• mutagen sensitivity of blood lymphocytes from women carrying brca2 mutatioon (PMID:11890937)
• Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany. (PMID:11897832)
• BRCA2 N372H polymorphism associated with modest recessively inherited risk of breast cancer in Australian women (PMID:11927503)
• somatic mutations in BRCA2 and high frequency of allelic loss occurs in sporadic male breast cancer (PMID:11948477)
• Expression of BRCA1 and BRCA2 in different tumor cell lines with various growth status (PMID:11983207)
• Cells from carriers of mutations in one allele of the BRCA1 or BRCA2 genes have no gross defects in their ability to rejoin radiation-induced DNA breaks. (PMID:12020440)
• cell lines derived from Fanconi anemia B and D1 patients have biallelic mutations in BRCA2 and express truncated BRCA2 proteins (PMID:12065746)
• BRCA2 exons 10 & 11 were studied by the protein truncation test, & BRCA2 exons 9, 17, 18 and 23 with the SSCP assay on genomic DNA from early-onset breast cancer patients by PCR. 2 frameshifts, 3 missense mutations, and a polymorphism were found. (PMID:12100744)
• Results demonstrate the importance of BRCA2 in the development of ovarian cancer in this Turkish population. (PMID:12112655)
• The 999del5 mutation in the BRCA2 gene explains a substantial proportion of familial risk of breast cancer in Iceland. (PMID:12114473)
• first BRCA2 missense mutation shown to be a predicted deleterious protein-truncating mutation and suggests a potentially useful method for determining the clinical significance of a subset of the many unclassified variants in BRCA1 and BRCA2 (PMID:12145750)
• Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan. (PMID:12181777)
• eight of the most common reported missense mutations in BRCA1 and BRCA2 occurring in patients tested for hereditary risk of breast and ovarian cancers (PMID:12215251)
• crystal structure of a COOH terminal BRCA2 domain bound to DSS1; demonstrate that this BRCA2 domain binds single-stranded DNA and show that BRCA2 stimulates RAD51-mediated recombination in vitro (PMID:12228710)
• relation of gene to various cancers, especially breast and ovarian cancers (PMID:12229875)
• inactivated in ovarian cancer (PMID:12237285)
• Survival in prospectively ascertained familial breast cancer: analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy (PMID:12237897)
• recent findings regarding BRCA2 in breast cancer - review (PMID:12242698)
• BBRCA2 gene mutation in unselected women with ovarian and early breast cancer in Mongolia predicts the genetic predisoposition to these diseases. (PMID:12440810)
• crystal structure of a complex between an evolutionarily conserved sequence in BRCA2 (the BRC repeat) and the RecA-homology domain of RAD51 (PMID:12442171)
• Two BRCA2 missense variants were identified in breast cancer patients in India. (PMID:12442273)
• BRCA2 mutation, 7883delTTAA, was identified in breast cancer patients in China. (PMID:12442274)
• BRCA2 2663-2664insA and rare variants were identified in breast cancer patients in Mexico. (PMID:12442275)
• Germline mutations in BRCA2 account for breast neoplasms predisposition in the majority of families. (PMID:12453858)
• highly recurrent BRCA2 splice site mutation (IVS16-2A>G) in three breast cancer-only families (PMID:12461697)
• BRCA2 has a more specific role in DNA repair, regulating the activity of RAD51(review) (PMID:12470990)
• cancer-predisposing mutation compromises interaction between BRCA2 and replication protein A (PMID:12527904)
• The BRCA2 gene plays a significant role in the familial breast cancer phenotype in the Cypriot population. (PMID:12552570)
• mutation analysis of this gene in a case of familial endometriosis (PMID:12568865)
• Our data support an important role for BRCA2 germline mutations in a subpopulation of families with familial pancreatic cancer. (PMID:12569143)
• S-phase RAD51 foci form normally in CAPAN-1 cells expressing truncated BRCA2. The observed BRCA2-dependent & independent formation of RAD51 foci shows that intact BRCA2 is not required for RAD51 focus formation per se. (PMID:12606939)
• BRCA2 germline mutation is associated with fallopian tube cancer. (PMID:12618335)
• polymorphisms in BRCA2 is associated with esophageal squamous cell carcinoma (PMID:12670525)
• Changes in the topoisomerase I activity in V-C8 cells are due to the defective function of the Brca2 gene. (PMID:12673354)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	brca2	ENSDARG00000079015
mus_musculus	Brca2	ENSMUSG00000041147
rattus_norvegicus	Brca2	ENSRNOG00000001111

Protein

Protein identifiers

Breast cancer type 2 susceptibility protein — P51587 (reviewed: P51587)

Alternative names: Fanconi anemia group D1 protein

All UniProt accessions (14): P51587, A0A590UJ24, A0A590UJI7, A0A590UJU6, A0A7P0T9D7, A0A7P0TAP7, A0A8V8TPZ2, A0A8V8TQQ4, A0AAQ5BGN0, A0AAQ5BGN2, A0AAQ5BGN4, A0AAQ5BGQ6, H0YD86, H0YE37

UniProt curated annotations — full annotation on UniProt →

Function. Involved in double-strand break repair and/or homologous recombination. Binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). Acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. Part of a PALB2-scaffolded HR complex containing RAD51C and which is thought to play a role in DNA repair by HR. May participate in S phase checkpoint activation. Binds selectively to ssDNA, and to ssDNA in tailed duplexes and replication fork structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with PALB2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity. In concert with NPM1, regulates centrosome duplication. Interacts with the TREX-2 complex (transcription and export complex 2) subunits PCID2 and SEM1, and is required to prevent R-loop-associated DNA damage and thus transcription-associated genomic instability. Silencing of BRCA2 promotes R-loop accumulation at actively transcribed genes in replicating and non-replicating cells, suggesting that BRCA2 mediates the control of R-loop associated genomic instability, independently of its known role in homologous recombination.

Subunit / interactions. Monomer and dimer. Interacts with RAD51; regulates RAD51 recruitment and function at sites of DNA repair. Interacts with WDR16, USP11, DMC1, ROCK2 and NPM1. Interacts with SEM1; the interaction masks a nuclear export signal in BRCA2. Interacts with both nonubiquitinated and monoubiquitinated FANCD2; this complex also includes XRCC3 and phosphorylated FANCG. Part of a BRCA complex containing BRCA1, BRCA2 and PALB2. Component of the homologous recombination repair (HR) complex composed of ERCC5/XPG, BRCA2, PALB2, DSS1 and RAD51. Within the complex, interacts with ERCC5/XPG and PALB2. Interacts directly with PALB2 which may serve as a scaffold for a HR complex containing PALB2, BRCA2, RAD51C, RAD51 and XRCC3. Interacts with BRCA1 only in the presence of PALB2 which serves as the bridging protein. Interacts with POLH; the interaction is direct. Interacts with the TREX-2 complex subunits PCID2 and SEM1. Interacts with HSF2BP and BRME1; the interaction with HSF2BP is direct and allows the formation of a ternary complex. The complex BRME1:HSF2BP:BRCA2 interacts with SPATA22, MEIOB and RAD51.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Highest levels of expression in breast and thymus, with slightly lower levels in lung, ovary and spleen.

Post-translational modifications. Phosphorylated by ATM upon irradiation-induced DNA damage. Phosphorylation by CHEK1 and CHEK2 regulates interaction with RAD51. Phosphorylation at Ser-3291 by CDK1 and CDK2 is low in S phase when recombination is active, but increases as cells progress towards mitosis; this phosphorylation prevents homologous recombination-dependent repair during S phase and G2 by inhibiting RAD51 binding. Ubiquitinated in the absence of DNA damage; this does not lead to proteasomal degradation. In contrast, ubiquitination in response to DNA damage leads to proteasomal degradation.

Disease relevance. Breast cancer (BC) [MIM:114480] A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Disease susceptibility is associated with variants affecting the gene represented in this entry. Pancreatic cancer 2 (PNCA2) [MIM:613347] A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. The disease is caused by variants affecting the gene represented in this entry. Breast-ovarian cancer, familial, 2 (BROVCA2) [MIM:612555] A condition associated with familial predisposition to cancer of the breast and ovaries. Characteristic features in affected families are an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific organs, such as the prostate. Disease susceptibility is associated with variants affecting the gene represented in this entry. Fanconi anemia complementation group D1 (FANCD1) [MIM:605724] A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. The disease is caused by variants affecting the gene represented in this entry. Glioma 3 (GLM3) [MIM:613029] Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. The disease is caused by variants affecting the gene represented in this entry. Medulloblastoma (MDB) [MIM:155255] Malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children. Disease susceptibility is associated with variants affecting the gene represented in this entry.

RefSeq proteins (6): NP_000050, NP_001393648, NP_001393649, NP_001393650, NP_001393651, NP_001419006 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002093	BRCA2_repeat	Repeat
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR015187	BRCA2_OB_1	Domain
IPR015188	BRCA2_OB_3	Domain
IPR015205	Tower_dom	Domain
IPR015252	BRCA2_hlx	Domain
IPR015525	BRCA2	Family
IPR036315	BRCA2_hlx_sf	Homologous_superfamily
IPR048262	BRCA2_OB_2_dom	Domain
IPR055077	BRCA2_TR2	Domain

Pfam: PF00634, PF09103, PF09104, PF09121, PF09169, PF21318, PF22687

UniProt features (213 total): sequence variant 160, region of interest 12, modified residue 10, repeat 8, strand 7, sequence conflict 5, helix 5, mutagenesis site 3, chain 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
8C3N	X-RAY DIFFRACTION	1.21
8BR9	X-RAY DIFFRACTION	1.63
1N0W	X-RAY DIFFRACTION	1.7
6HQU	X-RAY DIFFRACTION	1.97
3EU7	X-RAY DIFFRACTION	2.2
7LDG	X-RAY DIFFRACTION	2.56
7BDX	X-RAY DIFFRACTION	2.6
8PBC	ELECTRON MICROSCOPY	2.61
8UVW	X-RAY DIFFRACTION	2.73
8PBD	ELECTRON MICROSCOPY	2.83
8C3J	X-RAY DIFFRACTION	3.02
6GY2	X-RAY DIFFRACTION	3.11
8R2G	X-RAY DIFFRACTION	3.45
8QQE	X-RAY DIFFRACTION	3.46

Predicted structure (AlphaFold)

No AlphaFold model available for P51587 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (10): 70, 445, 492, 755, 1970, 2035, 2095, 3291, 3319, 3387

Mutagenesis-validated functional residues (3):

Position	Phenotype
2725	disrupts interaction with sem1.
3291	impaired interaction with rad51.
3387	loss of phosphorylation by chek1 and chek2 (in vitro).

Function

Pathways and Gene Ontology

Reactome pathways

27 pathways

ID	Pathway
R-HSA-5685939	HDR through MMEJ (alt-NHEJ)
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693554	Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)
R-HSA-5693568	Resolution of D-loop Structures through Holliday Junction Intermediates
R-HSA-5693579	Homologous DNA Pairing and Strand Exchange
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange
R-HSA-912446	Meiotic recombination
R-HSA-9701192	Defective homologous recombination repair (HRR) due to BRCA1 loss of function
R-HSA-9704331	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function
R-HSA-9704646	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function
R-HSA-9709275	Impaired BRCA2 translocation to the nucleus
R-HSA-9709570	Impaired BRCA2 binding to RAD51
R-HSA-9709603	Impaired BRCA2 binding to PALB2
R-HSA-9763198	Impaired BRCA2 binding to SEM1 (DSS1)
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-5693532	DNA Double-Strand Break Repair
R-HSA-5693537	Resolution of D-Loop Structures
R-HSA-5693538	Homology Directed Repair
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)
R-HSA-73894	DNA Repair
R-HSA-9675135	Diseases of DNA repair
R-HSA-9675136	Diseases of DNA Double-Strand Break Repair
R-HSA-9701190	Defective homologous recombination repair (HRR) due to BRCA2 loss of function
R-HSA-9701193	Defective homologous recombination repair (HRR) due to PALB2 loss of function

MSigDB gene sets: 832 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, PID_FANCONI_PATHWAY, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_RESPONSE_TO_UV_C, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, GOBP_REGULATION_OF_MAMMARY_GLAND_EPITHELIAL_CELL_PROLIFERATION, YAGI_AML_WITH_INV_16_TRANSLOCATION

GO Biological Process (38): telomere maintenance via recombination (GO:0000722), double-strand break repair via homologous recombination (GO:0000724), oocyte maturation (GO:0001556), inner cell mass cell proliferation (GO:0001833), nucleotide-excision repair (GO:0006289), double-strand break repair (GO:0006302), regulation of DNA-templated transcription (GO:0006355), male meiosis I (GO:0007141), spermatogenesis (GO:0007283), brain development (GO:0007420), female gonad development (GO:0008585), response to X-ray (GO:0010165), response to UV-C (GO:0010225), response to gamma radiation (GO:0010332), DNA damage response, signal transduction by p53 class mediator (GO:0030330), regulation of cytokinesis (GO:0032465), negative regulation of mammary gland epithelial cell proliferation (GO:0033600), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of mitotic cell cycle (GO:0045931), centrosome duplication (GO:0051298), establishment of protein localization to telomere (GO:0070200), hematopoietic stem cell proliferation (GO:0071425), cellular response to ionizing radiation (GO:0071479), cellular senescence (GO:0090398), mitotic recombination-dependent replication fork processing (GO:1990426), regulation of DNA damage checkpoint (GO:2000001), DNA repair (GO:0006281), DNA recombination (GO:0006310), chromatin remodeling (GO:0006338), DNA damage response (GO:0006974), cell population proliferation (GO:0008283), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), hemopoiesis (GO:0030097), replication fork processing (GO:0031297), chordate embryonic development (GO:0043009), chromosome organization (GO:0051276), stem cell proliferation (GO:0072089)

GO Molecular Function (8): protease binding (GO:0002020), single-stranded DNA binding (GO:0003697), histone H3 acetyltransferase activity (GO:0010484), histone H4 acetyltransferase activity (GO:0010485), identical protein binding (GO:0042802), gamma-tubulin binding (GO:0043015), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (14): nuclear ubiquitin ligase complex (GO:0000152), chromosome, telomeric region (GO:0000781), lateral element (GO:0000800), nucleus (GO:0005634), nucleoplasm (GO:0005654), centrosome (GO:0005813), cytosol (GO:0005829), secretory granule (GO:0030141), protein-containing complex (GO:0032991), BRCA2-MAGE-D1 complex (GO:0033593), DNA repair complex (GO:1990391), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	4
Resolution of D-Loop Structures	2
HDR through Homologous Recombination (HRR)	2
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2
Homology Directed Repair	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Homologous DNA Pairing and Strand Exchange	1
Meiosis	1
Diseases of DNA Double-Strand Break Repair	1
Reproduction	1
Cell Cycle	1
DNA Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
developmental process involved in reproduction	2
DNA repair	2
DNA-templated transcription	2
male gamete generation	2
response to ionizing radiation	2
histone acetyltransferase activity	2
intracellular membraneless organelle	2
telomere maintenance	1
mitotic recombination	1
recombinational repair	1
double-strand break repair	1
cell maturation	1
oocyte development	1
blastocyst growth	1
cell population proliferation	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
meiosis I	1
male meiotic nuclear division	1
meiotic cell cycle	1
central nervous system development	1
animal organ development	1
head development	1
gonad development	1
development of primary female sexual characteristics	1
response to UV	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
cytokinesis	1
regulation of cell cycle process	1
regulation of cell division	1
mammary gland epithelial cell proliferation	1
regulation of mammary gland epithelial cell proliferation	1
negative regulation of epithelial cell proliferation	1
negative regulation of multicellular organismal process	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
intrinsic apoptotic signaling pathway by p53 class mediator	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1

Protein interactions and networks

STRING

3778 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BRCA2	PALB2	Q86YC2	999
BRCA2	FANCD2	Q9BXW9	999
BRCA2	BRCA1	P38398	999
BRCA2	RAD51	Q06609	999
BRCA2	EMSY	Q7Z589	997
BRCA2	BARD1	Q99728	996
BRCA2	SEM1	Q6ZVN7	996
BRCA2	BCCIP	Q9P287	994
BRCA2	RAD52	P43351	991
BRCA2	FANCG	O15287	991
BRCA2	FANCI	Q9NVI1	988
BRCA2	XRCC3	O43542	988
BRCA2	RAD51C	O43502	976
BRCA2	BRIP1	Q9BX63	975
BRCA2	TP53	P04637	975

IntAct

301 interactions, top by confidence:

A	B	Type	Score
CCND1	CDK4	psi-mi:“MI:0914”(association)	0.990
BRCA2	RAD51	psi-mi:“MI:0915”(physical association)	0.980
RAD51	BRCA2	psi-mi:“MI:0915”(physical association)	0.980
BRCA2	RAD51	psi-mi:“MI:0407”(direct interaction)	0.980
RAD51	BRCA2	psi-mi:“MI:0407”(direct interaction)	0.980
BRCA2	RAD51	psi-mi:“MI:0403”(colocalization)	0.980
BRCA2	RAD51	psi-mi:“MI:0914”(association)	0.980
PALB2	BRCA2	psi-mi:“MI:0915”(physical association)	0.970
BRCA2	PALB2	psi-mi:“MI:0915”(physical association)	0.970
PALB2	BRCA2	psi-mi:“MI:0914”(association)	0.970
PALB2	BRCA1	psi-mi:“MI:0914”(association)	0.910

BioGRID (760): BRCA2 (Biochemical Activity), POLH (Affinity Capture-Western), POLH (Reconstituted Complex), POLH (Co-localization), BRCA2 (Affinity Capture-Western), BRCA2 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS), BRCA2 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LI88, A4D1E1, D3Z987, D3ZUC6, E5FYH0, E5FYH1, E9Q3S4, F6ULY3, F7DF15, G3S077, G7H7V7, G7NY55, O35923, O54952, O88491, O95405, P38398, P48754, P51587, P97929, Q0VBV7, Q0VGT4, Q2M3C7, Q3V089, Q56UN5, Q5DTT3, Q5F2C3, Q5VWN6, Q61493, Q68DQ2, Q6J6I8, Q6J6I9, Q6J6J0, Q6NSW3, Q6ZP01, Q7TSY8, Q7Z570, Q80U44, Q864S8, Q864U1

Diamond homologs: O35923, P51587, P97929, Q7Y1C4, Q7Y1C5, Q864S8

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
PLK1	“down-regulates activity”	BRCA2	phosphorylation
PALB2	up-regulates	BRCA2	binding
BRCA2	up-regulates	POLH	binding
PLK1	unknown	BRCA2	phosphorylation
BRCA2	“up-regulates activity”	RAD51	binding
BRCA2	“form complex”	“BRCC ubiquitin ligase complex”	binding
FANCD2	“up-regulates activity”	BRCA2	binding
FANCD2	“up-regulates activity”	BRCA2	relocalization
BRCA2	“form complex”	“D1-D2-G-X3 complex”	binding
EMSY	“down-regulates activity”	BRCA2	binding
“Fanconi anemia ID complex”	up-regulates	BRCA2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 137 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
HSF1 activation	6	26.6×	3e-05
Attenuation phase	5	23.7×	3e-04
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	5	22.9×	3e-04
HSF1-dependent transactivation	6	22.1×	7e-05
Homologous DNA Pairing and Strand Exchange	5	22.1×	3e-04
Impaired BRCA2 binding to RAD51	5	17.9×	6e-04
HDR through Homologous Recombination (HRR)	8	17.7×	1e-05
Resolution of D-loop Structures through Holliday Junction Intermediates	5	17.5×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
response to unfolded protein	6	14.7×	5e-04
double-strand break repair via homologous recombination	10	12.7×	5e-06
positive regulation of protein ubiquitination	5	8.7×	9e-03
protein folding	9	7.6×	5e-04
DNA damage response	15	6.5×	5e-06
regulation of apoptotic process	9	6.1×	1e-03
regulation of cell cycle	10	6.1×	7e-04
protein stabilization	10	5.4×	1e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

BRCA2 mutations in the germline have become a hallmark for hereditary breast and ovarian cancers. Variants that have been demonstrated to reduce the function of the protein have been shown to increase the risk for these cancers, as well as prostate and pancreatic cancer. These findings have been the impetus for the increased popularity of genetic testing of healthy individuals to assess risk. Recent studies in ovarian cancer have also demonstrated that BRCA mutation status can predict treatment response. A number of trials assessing BRCA mutation status have shown an improved response to platinum agents, and more recently has led to the FDA-approval of PARP inhibitors for BRCA-positive ovarian cancers. These studies have resulted in the Society of Gynecologic Oncology to recommend germline BRCA testing in all patients with a diagnosis of ovarian cancer.

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 14 cancer types — BLCA, BRCA, CESC, CHOL, HCC, HNSC, LUSC, MBL, OVT, PAAD, PRAD, PROSTATE…(+2 more).

Clinical variants and AI predictions

ClinVar

21654 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5115
Likely pathogenic	408
Uncertain significance	4299
Likely benign	4808
Benign	800

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012157	NM_000059.4(BRCA2):c.9163del (p.Leu3055fs)	Pathogenic
1012158	NM_000059.4(BRCA2):c.5934del (p.Phe1978fs)	Pathogenic
1012159	NM_000059.4(BRCA2):c.5566_5567inv (p.His1856Cys)	Pathogenic
1012160	NM_000059.4(BRCA2):c.5362del (p.Ser1788fs)	Pathogenic
1012161	NM_000059.4(BRCA2):c.5297del (p.Asn1766fs)	Pathogenic
1012162	NM_000059.4(BRCA2):c.1561del (p.Ser521fs)	Pathogenic
1012164	NM_000059.4(BRCA2):c.728del (p.Asn243fs)	Pathogenic
1012165	NM_000059.4(BRCA2):c.691_692delinsGA (p.Ser231Asp)	Pathogenic
1012166	NM_000059.4(BRCA2):c.2588del (p.Asn863fs)	Pathogenic
1012167	NM_000059.4(BRCA2):c.7177del (p.Lys2392_Met2393insTer)	Pathogenic
1012168	NM_000059.4(BRCA2):c.10248del (p.Lys3416fs)	Pathogenic
1012202	NM_000059.4(BRCA2):c.8423_8427delinsA (p.Leu2808fs)	Pathogenic
1012203	NM_000059.4(BRCA2):c.8487+2T>G	Pathogenic
1012631	NM_000059.4(BRCA2):c.1490_1493del (p.Ser497fs)	Pathogenic
1048907	NM_000059.4(BRCA2):c.68-2_316+1del	Pathogenic
1048937	NM_000059.4(BRCA2):c.517-2_631+1del	Pathogenic
1048980	NM_000059.4(BRCA2):c.4042del (p.Cys1348fs)	Pathogenic
1049319	NM_000059.4(BRCA2):c.7436-2_7617+189del	Pathogenic
1049351	NM_000059.4(BRCA2):c.6808_6836del (p.Gly2270fs)	Pathogenic
1049419	NM_000059.4(BRCA2):c.1859_1865del (p.Gln619_Phe620insTer)	Pathogenic
1049456	NM_000059.4(BRCA2):c.8732del (p.Ala2911fs)	Pathogenic
1049566	NM_000059.4(BRCA2):c.3119del (p.Thr1040fs)	Pathogenic
1050075	NM_000059.4(BRCA2):c.8332-1_8487+146dup	Pathogenic
1050270	NM_000059.4(BRCA2):c.8469_8475del (p.Gln2823fs)	Pathogenic
1050378	NM_000059.4(BRCA2):c.8755-2_9023del	Pathogenic
1050481	NM_000059.4(BRCA2):c.6334A>T (p.Arg2112Ter)	Pathogenic
1050553	NM_000059.4(BRCA2):c.8827del (p.Gln2943fs)	Pathogenic
1050639	NM_000059.4(BRCA2):c.5593dup (p.Ile1865fs)	Pathogenic
1050735	NM_000059.4(BRCA2):c.7726G>T (p.Gly2576Ter)	Pathogenic
1068327	NC_000013.10:g.(?32944519)(32944714_?)del	Pathogenic

SpliceAI

3855 predictions. Top by Δscore:

Variant	Effect	Δscore
13:32315664:GCGG:G	donor_gain	1.0000
13:32326099:A:AG	acceptor_gain	1.0000
13:32326100:G:GG	acceptor_gain	1.0000
13:32326100:GTCCT:G	acceptor_gain	1.0000
13:32326240:A:AG	acceptor_gain	1.0000
13:32326240:AGT:A	acceptor_gain	1.0000
13:32326241:G:GA	acceptor_gain	1.0000
13:32326241:GTG:G	acceptor_gain	1.0000
13:32326241:GTGGT:G	acceptor_gain	1.0000
13:32326565:TC:T	donor_gain	1.0000
13:32329439:ACAG:A	acceptor_loss	1.0000
13:32329440:CA:C	acceptor_loss	1.0000
13:32329441:A:AG	acceptor_gain	1.0000
13:32329441:AGT:A	acceptor_loss	1.0000
13:32329442:G:GA	acceptor_gain	1.0000
13:32329442:GTC:G	acceptor_gain	1.0000
13:32329442:GTCA:G	acceptor_gain	1.0000
13:32329488:CTGCT:C	donor_gain	1.0000
13:32329490:GCT:G	donor_gain	1.0000
13:32329491:CT:C	donor_gain	1.0000
13:32329492:TG:T	donor_loss	1.0000
13:32329493:G:GG	donor_gain	1.0000
13:32329493:GTA:G	donor_loss	1.0000
13:32329494:T:A	donor_loss	1.0000
13:32329497:G:GG	donor_gain	1.0000
13:32330913:TTGCA:T	acceptor_loss	1.0000
13:32330914:TGCA:T	acceptor_loss	1.0000
13:32330915:GCA:G	acceptor_loss	1.0000
13:32330917:A:AG	acceptor_gain	1.0000
13:32330917:AGAAT:A	acceptor_gain	1.0000

AlphaMissense

22763 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:32326562:T:A	W194R	0.997
13:32326562:T:C	W194R	0.997
13:32362684:T:C	L2656P	0.996
13:32370993:G:C	R2842P	0.993
13:32319100:T:A	W31R	0.992
13:32319100:T:C	W31R	0.992
13:32326564:G:C	W194C	0.991
13:32326564:G:T	W194C	0.991
13:32362572:T:A	W2619R	0.991
13:32362572:T:C	W2619R	0.991
13:32326568:A:C	S196R	0.990
13:32326570:T:A	S196R	0.990
13:32326570:T:G	S196R	0.990
13:32362693:G:C	R2659T	0.990
13:32398405:T:C	F3298L	0.990
13:32398407:T:A	F3298L	0.990
13:32398407:T:G	F3298L	0.990
13:32337734:T:C	F1127L	0.989
13:32337736:T:A	F1127L	0.989
13:32337736:T:G	F1127L	0.989
13:32362602:T:A	W2629R	0.989
13:32362602:T:C	W2629R	0.989
13:32363179:A:C	R2659S	0.989
13:32363179:A:T	R2659S	0.989
13:32363529:T:C	L2776S	0.988
13:32380116:G:A	G3076E	0.988
13:32394806:T:C	L3125P	0.988
13:32362528:T:C	L2604P	0.987
13:32363369:G:C	D2723H	0.987
13:32376756:G:C	A2907P	0.987

dbSNP variants (sampled 300 via entrez): RS1000097191 (13:32344268 A>G), RS1000102679 (13:32383636 G>A), RS1000266990 (13:32328863 G>A), RS1000274150 (13:32374391 A>G,T), RS1000343210 (13:32350857 A>G), RS1000373744 (13:32396174 A>G,T), RS1000397919 (13:32380820 G>A), RS1000398743 (13:32337399 A>C,G,T), RS1000452019 (13:32380665 C>A,T), RS1000452381 (13:32335711 T>C), RS1000515665 (13:32362105 C>T), RS1000568331 (13:32330734 G>A), RS1000593672 (13:32363786 G>C), RS1000645994 (13:32374694 A>G), RS1000705954 (13:32354918 A>C,G,T)

Disease associations

OMIM: gene MIM:600185 | disease phenotypes: MIM:612555, MIM:114480, MIM:604370, MIM:155255, MIM:194070, MIM:605724, MIM:613029, MIM:613347, MIM:176807, MIM:260350, MIM:613659, MIM:262400, MIM:167000, MIM:215400, MIM:601228, MIM:114500, MIM:109800, MIM:227650, MIM:608089, MIM:254500, MIM:189960, MIM:192600, MIM:603596, MIM:133239, MIM:147920, MIM:614327, MIM:155600

GenCC curated gene-disease

Disease	Classification	Inheritance
Fanconi anemia complementation group D1	Definitive	Autosomal recessive
breast-ovarian cancer, familial, susceptibility to, 2	Definitive	Autosomal dominant
BRCA2-related cancer predisposition	Definitive	Autosomal dominant
pancreatic cancer, susceptibility to, 2	Strong	Autosomal dominant
sarcoma	Moderate	Autosomal dominant
hereditary breast ovarian cancer syndrome	Supportive	Autosomal dominant
Fanconi anemia	Supportive	Autosomal recessive
medulloblastoma	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Fanconi anemia complementation group D1	Definitive	AR
BRCA2-related cancer predisposition	Definitive	AD

Mondo (69): hereditary breast ovarian cancer syndrome (MONDO:0003582), hereditary neoplastic syndrome (MONDO:0015356), breast-ovarian cancer, familial, susceptibility to, 2 (MONDO:0012933), hereditary breast carcinoma (MONDO:0016419), BRCA2-related cancer predisposition (MONDO:0700269), breast-ovarian cancer, familial, susceptibility to, 1 (MONDO:0011450), breast cancer (MONDO:0007254), colon carcinoma (MONDO:0002032), exocrine pancreatic carcinoma (MONDO:0005192), medulloblastoma (MONDO:0007959), Wilms tumor 1 (MONDO:0008679), Fanconi anemia complementation group D1 (MONDO:0011584), glioma susceptibility 3 (MONDO:0013093), pancreatic cancer, susceptibility to, 2 (MONDO:0013235), prostate cancer, hereditary (MONDO:0700275)

Orphanet (41): Inherited cancer-predisposing syndrome (Orphanet:140162), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Hereditary breast cancer (Orphanet:227535), Familial pancreatic carcinoma (Orphanet:1333), Rare carcinoma of pancreas (Orphanet:217074), Familial prostate cancer (Orphanet:1331), Glial tumor (Orphanet:182067), Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations (Orphanet:319462), Glioblastoma (Orphanet:360), Medulloblastoma (Orphanet:616), Nephroblastoma (Orphanet:654), Isolated growth hormone deficiency type IA (Orphanet:231662), Non-acquired isolated growth hormone deficiency (Orphanet:631), Rare ovarian cancer (Orphanet:213500), Pilocytic astrocytoma (Orphanet:251612)

HPO phenotypes

217 total (30 of 217 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000035	Abnormal testis morphology
HP:0000047	Hypospadias
HP:0000072	Hydroureter
HP:0000079	Abnormality of the urinary system
HP:0000083	Renal insufficiency
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000130	Abnormality of the uterus
HP:0000135	Hypogonadism
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000364	Hearing abnormality
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000453	Choanal atresia
HP:0000478	Abnormality of the eye
HP:0000483	Astigmatism

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST001930_11	Breast cancer	6.000000e-06
GCST001937_19	Breast cancer	5.000000e-08
GCST002222_22	LDL cholesterol	2.000000e-11
GCST002466_1	Lung cancer	2.000000e-19
GCST002466_3	Lung cancer	5.000000e-20
GCST003587_12	Cancer	8.000000e-12
GCST003588_18	Cancer (pleiotropy)	5.000000e-10
GCST004233_11	LDL cholesterol levels	5.000000e-14
GCST004233_27	LDL cholesterol levels	3.000000e-09
GCST004236_11	LDL cholesterol levels	3.000000e-08
GCST004746_39	Small cell lung carcinoma	3.000000e-08
GCST004748_27	Lung cancer	6.000000e-16
GCST004749_35	Lung cancer in ever smokers	6.000000e-08
GCST004750_40	Squamous cell lung carcinoma	1.000000e-15
GCST004988_25	Breast cancer	3.000000e-15
GCST008870_38	Keratinocyte cancer (MTAG)	6.000000e-10
GCST008871_8	Basal cell carcinoma	2.000000e-09
GCST008872_5	Squamous cell carcinoma	1.000000e-09
GCST010148_24	Cutaneous squamous cell carcinoma	1.000000e-06
GCST010243_161	Apolipoprotein B levels	3.000000e-27
GCST010245_175	LDL cholesterol levels	4.000000e-15

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:1001515	ovarian endometrioid carcinoma
EFO:1001516	ovarian serous carcinoma
EFO:0010176	keratinocyte carcinoma
EFO:1001927	cutaneous squamous cell carcinoma
EFO:0004615	apolipoprotein B measurement

MeSH disease descriptors (30)

Descriptor	Name	Tree numbers
D001943	Breast Neoplasms	C04.588.180; C17.800.090.500
D018567	Breast Neoplasms, Male	C04.588.180.260; C17.800.090.500.260
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D002547	Cerebral Palsy	C10.228.140.140.254
D002817	Chordoma	C04.557.465.220
D000080443	Diffuse Intrinsic Pontine Glioma	C04.557.465.625.600.380.185; C04.557.470.670.380.185; C04.557.580.625.600.380.185; C04.588.614.250.195.411.100.500; C10.228.140.211.500.100.500; C10.551.240.250.400.200.500
D005199	Fanconi Anemia	C15.378.050.085.080.280; C15.378.190.223.500.500.280; C16.320.077.280; C18.452.284.280
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D018197	Hepatoblastoma	C04.557.435.380
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D016403	Lymphoma, Large B-Cell, Diffuse	C04.557.386.480.150.585; C15.604.515.569.480.150.585; C20.683.515.761.480.150.585
D008527	Medulloblastoma	C04.557.465.625.600.380.515; C04.557.465.625.600.590.500; C04.557.470.670.380.515; C04.557.470.670.590.500; C04.557.580.625.600.380.515; C04.557.580.625.600.590.500
D008545	Melanoma	C04.557.465.625.650.510; C04.557.580.625.650.510; C04.557.665.510; C04.588.805.377; C17.800.882.445
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D009447	Neuroblastoma	C04.557.465.625.600.590.650.550; C04.557.470.670.590.650.550; C04.557.580.625.600.590.650.550
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D017689	Polydactyly	C05.660.585.600; C16.131.621.585.600
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D012208	Rhabdomyosarcoma	C04.557.450.590.550.660; C04.557.450.795.550.660
D012509	Sarcoma	C04.557.450.795
D009396	Wilms Tumor	C04.557.435.595; C04.588.945.947.535.585; C04.700.900; C12.050.351.937.820.535.585; C12.050.351.968.419.473.585; C12.200.758.820.750.585; C12.200.777.419.473.585; C12.900.820.535.585; C12.950.419.473.585; C12.950.983.535.585; C16.320.700.900
C562840	Breast Cancer, Familial (supp.)
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)
C563980	Fanconi Anemia, Complementation Group D1 (supp.)
C535837	Pancreatic carcinoma, familial (supp.)
C537404	Pituitary dwarfism 1 (supp.)
C537243	Prostate cancer, familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 51 predictive associations from 63 curated evidence items; also 3 prognostic, 2 predisposing, 1 functional.

Variant	Therapy	Indication	Effect	Level	CIViC
BRCA2 Mutation	Rucaparib	Ovarian Cancer	Sensitivity/Response	CIViC A	EID11137 +3
BRCA2 Mutation	Olaparib	Ovarian Cancer	Sensitivity/Response	CIViC A	EID7276 +2
BRCA2 Mutation	Olaparib	Prostate Cancer	Sensitivity/Response	CIViC A	EID12942 +2
BRCA2 Loss-of-function	Olaparib	Her2-receptor Negative Breast Cancer	Sensitivity/Response	CIViC A	EID11202 +1
BRCA1 Mutation OR BRCA2 Mutation	Niraparib	Epithelial Ovarian Cancer	Sensitivity/Response	CIViC A	EID11243
BRCA1 Mutation OR BRCA2 Mutation	Rucaparib	Fallopian Tube, Ovarian Cancer, And Peritoneal Serous Carcinoma	Sensitivity/Response	CIViC A	EID11246
BRCA1 Mutation OR BRCA2 Mutation	Niraparib	Peritoneal Carcinoma	Sensitivity/Response	CIViC A	EID11304
BRCA1 Mutation OR BRCA2 Mutation	Niraparib	Fallopian Tube Carcinoma	Sensitivity/Response	CIViC A	EID11305
BRCA1 Mutation OR BRCA2 Mutation	Abiraterone + Niraparib	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC A	EID11738
BRCA1 Mutation OR BRCA2 Mutation	Rucaparib	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC A	EID12944
BRCA2 Loss-of-function	Olaparib	Triple-receptor Negative Breast Cancer	Sensitivity/Response	CIViC A	EID11217
BRCA2 Loss-of-function	Olaparib	Pancreatic Adenocarcinoma	Sensitivity/Response	CIViC A	EID7385
BRCA2 Mutation	Talazoparib + Enzalutamide	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC A	EID11733
BRCA2 Mutation	Olaparib	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC A	EID8842
BRCA2 Mutation	Rucaparib	Pancreatic Cancer	Sensitivity/Response	CIViC B	EID7436 +3
BRCA2 Mutation	Platinum Compound	Ovarian Carcinoma	Sensitivity/Response	CIViC B	EID1530 +1
BRCA1 Mutation OR BRCA2 Mutation	Olaparib	Prostate Cancer	Sensitivity/Response	CIViC B	EID11666
BRCA1 Mutation OR BRCA2 Mutation	Olaparib	Breast Carcinoma	Sensitivity/Response	CIViC B	EID12763
BRCA1 Mutation OR BRCA2 Mutation	Olaparib	Biliary Tract Cancer	Sensitivity/Response	CIViC B	EID12764
BRCA1 Mutation OR BRCA2 Mutation	Olaparib	Lung Carcinoma	Sensitivity/Response	CIViC B	EID12765
BRCA1 Mutation OR BRCA2 Mutation	Olaparib	Uterine Cancer	Sensitivity/Response	CIViC B	EID12766
BRCA1 Mutation OR BRCA2 Mutation	Olaparib	Solid Tumor	Sensitivity/Response	CIViC B	EID12767
BRCA2 Loss-of-function	Olaparib	Ovarian Cancer	Sensitivity/Response	CIViC B	EID212
BRCA2 Loss-of-function	Talazoparib	Breast Cancer	Sensitivity/Response	CIViC B	EID4839
BRCA2 Loss-of-function	Talazoparib	Ovarian Cancer	Sensitivity/Response	CIViC B	EID4875
BRCA2 Loss-of-function	Olaparib	Prostate Cancer	Sensitivity/Response	CIViC B	EID650
BRCA2 Mutation	Olaparib	Her2-receptor Negative Breast Cancer	Sensitivity/Response	CIViC B	EID11425
BRCA2 Mutation	Olaparib	Cancer	Sensitivity/Response	CIViC B	EID1371
BRCA2 Mutation	Cediranib + Olaparib	Ovarian Cancer	Sensitivity/Response	CIViC B	EID1678
BRCA2 Mutation	Carboplatin + Cisplatin	Triple-receptor Negative Breast Cancer	Sensitivity/Response	CIViC B	EID1685

+21 more predictive associations (showing top 30 by evidence level).

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

2 measured of 2 human assays (2 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
N-cyclopentyl-2-((5-((2-oxobenzo[d]thiazol-3(2H)-yl)methyl)-4-phenpropyl-4H-1,2,4-triazol-3-yl)thio)acetamide	EC50	25000 nM
F0665-0303	EC50	53000 nM

CTD chemical–gene interactions

119 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases expression, increases methylation, increases expression, increases reaction	5
Resveratrol	affects cotreatment, increases expression, decreases expression	4
Cisplatin	decreases response to substance, increases expression	4
lasiocarpine	decreases expression, increases metabolic processing, increases expression	3
Benzo(a)pyrene	affects methylation, increases expression	3
Endosulfan	affects expression, decreases reaction, decreases expression, increases expression	3
Oxygen	affects cotreatment, decreases reaction, increases expression, decreases expression	3
Valproic Acid	affects expression, decreases expression	3
Cyclosporine	decreases expression	3
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	3
trichostatin A	affects cotreatment, affects expression, decreases expression	2
sodium arsenite	increases expression	2
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride	decreases expression	2
Bortezomib	affects cotreatment, increases expression, decreases expression	2
Arsenic Trioxide	affects cotreatment, increases expression, decreases expression	2
Benzene	affects expression, increases response to substance	2
Cannabidiol	decreases reaction, increases expression, decreases expression, affects cotreatment	2
Doxorubicin	decreases expression	2
Gold	decreases expression, affects binding	2
Nitrogen Mustard Compounds	decreases reaction, increases expression, decreases expression	2
Quercetin	affects cotreatment, decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
Tretinoin	decreases expression, affects expression	2
Aflatoxin B1	affects expression, increases expression	2
GSK-J4	decreases expression	1
TAK-243	decreases sumoylation	1
methylmercuric chloride	decreases expression	1
naringenin	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
1,12-benzoperylene	increases expression	1

Cellosaurus cell lines

2,123 cell lines: 2,087 cancer cell line, 21 transformed cell line, 8 induced pluripotent stem cell, 3 finite cell line, 2 telomerase immortalized cell line, 2 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0179	BT-474	Cancer cell line	Female
CVCL_0237	Capan-1	Cancer cell line	Male
CVCL_0291	HCT 116	Cancer cell line	Male
CVCL_0292	HCT 15	Cancer cell line	Male
CVCL_0620	MDA-MB-361	Cancer cell line	Female
CVCL_0A59	Capan1M9	Cancer cell line	Male
CVCL_1114	CAL-85-1	Cancer cell line	Female
CVCL_1255	HCC1569	Cancer cell line	Female
CVCL_1304	IGROV-1	Cancer cell line	Female
CVCL_1331	KM12	Cancer cell line	Male

Clinical trials (associated diseases)

599 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02875314	PHASE4	ACTIVE_NOT_RECRUITING	HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors
NCT04081701	PHASE4	RECRUITING	68-Ga DOTATATE PET/MRI in the Diagnosis and Management of Somatostatin Receptor Positive CNS Tumors.
NCT03144206	PHASE4	ACTIVE_NOT_RECRUITING	Hyperbaric Oxygen Therapy for Soft Tissue Sarcoma Pilot Study
NCT03244020	PHASE4	ENROLLING_BY_INVITATION	LMWH vs Aspirin for VTE Prophylaxis in Orthopaedic Oncology
NCT04033081	PHASE4	ACTIVE_NOT_RECRUITING	Registry of Sarcoma Patients Treated With Permanently Implantable LDR CivaSheet®
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	PHASE4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	PHASE4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	PHASE4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	PHASE4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	PHASE4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD