XRCC2

Summary

XRCC2 (X-ray repair cross complementing 2, HGNC:12829) is a protein-coding gene on chromosome 7q36.1, encoding DNA repair protein XRCC2 (O43543). Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions. It is a selective cancer dependency (DepMap: 44.1% of cell lines).

This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene is involved in the repair of DNA double-strand breaks by homologous recombination and it functionally complements Chinese hamster irs1, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents.

Source: NCBI Gene 7516 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fanconi anemia complementation group U (Moderate, GenCC) — +7 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 856 total — 2 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 131
• Cancer dependency (DepMap): dependent in 44.1% of screened cell lines
• MANE Select transcript: NM_005431

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12829
Approved symbol	XRCC2
Name	X-ray repair cross complementing 2
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Aliases	FANCU
Ensembl gene	ENSG00000196584
Ensembl biotype	protein_coding
OMIM	600375
Entrez	7516

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000359321, ENST00000495707, ENST00000698506, ENST00000698507

RefSeq mRNA: 1 — MANE Select: NM_005431 NM_005431

CCDS: CCDS5933

Canonical transcript exons

ENST00000359321 — 3 exons

Exon	Start	End
ENSE00001199032	152676041	152676141
ENSE00001289914	152644776	152649363
ENSE00003662020	152660701	152660782

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.9388 / max 276.5256, expressed in 1273 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86990	6.6137	1239
86989	1.3252	585

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	99.07	gold quality
tendon of biceps brachii	UBERON:0008188	91.77	gold quality
lateral globus pallidus	UBERON:0002476	90.56	gold quality
sperm	CL:0000019	89.31	gold quality
pylorus	UBERON:0001166	89.00	gold quality
male germ cell	CL:0000015	88.65	gold quality
subthalamic nucleus	UBERON:0001906	88.51	gold quality
inferior vagus X ganglion	UBERON:0005363	88.48	gold quality
substantia nigra pars reticulata	UBERON:0001966	88.45	gold quality
cardia of stomach	UBERON:0001162	88.41	gold quality
ventral tegmental area	UBERON:0002691	88.01	gold quality
superior surface of tongue	UBERON:0007371	87.73	gold quality
substantia nigra pars compacta	UBERON:0001965	87.61	gold quality
renal medulla	UBERON:0000362	87.53	gold quality
lateral nuclear group of thalamus	UBERON:0002736	87.40	gold quality
pericardium	UBERON:0002407	86.95	gold quality
superior vestibular nucleus	UBERON:0007227	86.28	gold quality
dorsal plus ventral thalamus	UBERON:0001897	86.09	gold quality
trigeminal ganglion	UBERON:0001675	85.78	gold quality
nipple	UBERON:0002030	85.50	gold quality
pancreatic ductal cell	CL:0002079	84.81	silver quality
globus pallidus	UBERON:0001875	84.57	gold quality
vena cava	UBERON:0004087	84.48	silver quality
medulla oblongata	UBERON:0001896	84.36	gold quality
pharyngeal mucosa	UBERON:0000355	84.23	gold quality
synovial joint	UBERON:0002217	83.97	gold quality
body of tongue	UBERON:0011876	83.72	gold quality
mucosa of paranasal sinus	UBERON:0005030	83.51	gold quality
tongue	UBERON:0001723	83.34	gold quality
medial globus pallidus	UBERON:0002477	83.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	81.47
E-ANND-3	yes	4.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, MYC, MYCN

miRNA regulators (miRDB)

79 targeting XRCC2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-766-3P	99.47	65.24	1811

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 44.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Homologous pairing and ring and filament structure formation activities of the human Xrcc2*Rad51D complex. (PMID:11834724)
• a critical role in homologous recombination repair (PMID:14645207)
• hXRCC2 enhances ADP/ATP processing and strand exchange by hRAD51 (PMID:15123651)
• Finds no association between XRCC2 R188H polymorphism and risk of colorectal adenoma. (PMID:15184273)
• Considering that the XRCC2 (R188H) allele reduces risk to epithelial ovarian cancer, the increased XRCC2 activity with the R188H polymorphism may have clinical benefit in preventing cancer risk. (PMID:17141189)
• possible association of single nucleotide polymorphism at the 41657C/T position and 4234G/C position of XRCC2 with susceptibility to esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) (PMID:17922422)
• polymorphism may be one of the genetic modifiers for smoking-related pancreatic cancer (PMID:17986315)
• investigated the possible association of three SNPs, XRCC2 C41657T, XRCC2 G4234C and XRCC3 A17893G with susceptibility to esophageal squamous cell carcinoma and gastric cardia adenocarcinoma in a population of northern China (PMID:18046624)
• genetic variation in SNPs in XRCC1 and XRCC2 genes, but not XRCC3, may influence breast cancer susceptibility (PMID:18188695)
• Findings suggest that the heterozygous and homozygous T allele of the XRCC4 G-1394T may be associated with the development of breast cancer (PMID:18383855)
• combined XRCCs 1-4 polymorphisms associated with oral cancer risk (PMID:18410587)
• The snp XRCC2 rs3218536 showd some evidence of a protective association for the rare allele in progesterone receptor positive breast neoplasms. (PMID:19064565)
• Investigation supports a role for XRCC2 in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors. (PMID:19690184)
• may influence the repair capacity of breast cancer patients and, in turn, confer genetic predisposition to disease (PMID:20004634)
• the present meta-analysis suggests that the XRCC2 Arg188His is not directly associated with breast cancer risk (PMID:20127279)
• An important function of XRCC2 is to enhance the activity of RAD51, so that the loss of XRCC2 results in a severe delay in the early response of RAD51 to DNA damage. (PMID:20189471)
• The Arg188His polymorphism of the XRCC2 gene can modify the risk of colorectal cancer. (PMID:21104022)
• Data show that XRCC2 and other homologous recombination proteins, including the key recombinase RAD51, co-localize with the centrosome, potentially to coordinate the deployment of a DNA damage response at vulnerable phases of the cell cycle. (PMID:21276791)
• These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival. (PMID:21632523)
• polymorphisms in XRCC2 do not contribute to cancer risk in a population of Lynch syndrome patients with colorectal cancer (PMID:21974800)
• The identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia. (PMID:22464251)
• The results support the hypothesis that polymorphism of XRCC2 may be associated with the incidence of sporadic breast cancer in Polish women. (PMID:22611952)
• Our data do not confirm an association between XRCC2 variants and breast cancer risk, although a relative risk smaller than two could not be excluded. (PMID:23054243)
• Studied whether the double strand break gene polymorphisms XRCC2 R188H G>A (rs3218536), XRCC3 T241M C>T (rs861539) and R243H G>A (rs77381814) are associated with cervical cancer in Argentine women. (PMID:23539294)
• Genetic variants in XRCC2 are not associated with soft-tissue sarcoma. (PMID:24189466)
• current meta-analysis indicated that the Arg188His polymorphism in the XRCC2 gene might be a risk factor for ovarian cancer (PMID:24414483)
• Our data suggest that the suppression of XRCC2 expression rendered colon tumor cells more sensitive to radiation therapy in vitro and in vivo. (PMID:24481064)
• impact of XRCC2 Arg188His polymorphism on cancer susceptibility (PMID:24621646)
• In conclusion, XRCC2 Arg188His and XRCC3 Thr241Met polymorphisms may be regarded as predictive factors of triple-negative breast cancer in female population. (PMID:24728564)
• Interaction of tobacco and polymorphisms of XRCC1 and XRCC2 increases the risk of head and neck squamous cell carcinoma in northeast Indian population.The XRCC2 Arg188His polymorphism was associated with increased risk of this cancer. (PMID:24958516)
• Our data suggests that deregulation of XRCC2 in breast cancer has the potential to predict lymph node metastasis (PMID:25159888)
• XRCC2 protein expression of colorectal cancer Chinese Han patients with CT/TT genotypes were significantly higher than CC genotype. (PMID:25304007)
• A relationship was identified between XRCC2-41657C/T polymorphism and the incidence of ovarian cancer. (PMID:25355640)
• Single nucleotide changes were studied in XRCC2 and XRCC3 genes at locus Arg188His and Thr241Met in stomach cancer patients who lived in North Eastern Turkey and in controls. (PMID:25428673)
• High XRCC2 expression promotes CRC cell proliferation and enriches cells in the G0/G1 phase but inhibits apoptosis. (PMID:25526472)
• The GA genotype of the Arg188His polymorphism of XRCC2 was associated with increased risk of breast cancer in a Pakistani cohort. (PMID:25556451)
• Links the SNP -41657C/T (rs718282) of the XRCC2 gene with endometrial carcinoma in Polish women. (PMID:26017882)
• involvement of ZNF281 in the cellular response to genotoxic stress through the control exercised on the expression of genes that act in different repair mechanisms (PMID:26300006)
• Suggest that XRCC2 is a useful predictive biomarker of preoperative radiotherapy treatment response in locally advanced rectal cancer patients. (PMID:26320178)
• The aim of the present study was to evaluate the relationship between prostate cancer risk and the presence of single nucleotide polymorphisms in the genes involved in Homologous recombination repair, RAD51, RAD51B, XRCC2 and XRCC3. (PMID:26339569)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	XRCC2	ENSDARG00000013933
mus_musculus	Xrcc2	ENSMUSG00000028933
rattus_norvegicus	Xrcc2	ENSRNOG00000007493

Paralogs (6): RAD51 (ENSG00000051180), DMC1 (ENSG00000100206), RAD51C (ENSG00000108384), XRCC3 (ENSG00000126215), RAD51B (ENSG00000182185), RAD51D (ENSG00000185379)

Protein

Protein identifiers

DNA repair protein XRCC2 — O43543 (reviewed: O43543)

Alternative names: X-ray repair cross-complementing protein 2

All UniProt accessions (3): O43543, A0A384MEK2, A0A8V8TMB7

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions. Part of the RAD51 paralog protein complex BCDX2 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 binds predominantly to the intersection of the four duplex arms of the Holliday junction and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA.

Subunit / interactions. Interacts with RAD51D. Part of the BCDX2 complex consisting of RAD51B, RAD51C, RAD51D and XRCC2; the complex has a ring-like structure arranged into a flat disk around a central channel. In the absence of DNA, the BCDX2 subcomplex XRCC2:RAD51D formed a multimeric ring structure; in the presence of single-stranded DNA it formed a filamentous structure with the ssDNA.

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

Disease relevance. Fanconi anemia, complementation group U (FANCU) [MIM:617247] 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. Spermatogenic failure 50 (SPGF50) [MIM:619145] An autosomal recessive infertility disorder characterized by azoospermia due to meiotic arrest at the zygotene stage of prophase I. The disease is caused by variants affecting the gene represented in this entry. Premature ovarian failure 17 (POF17) [MIM:619146] A form of premature ovarian failure, an ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. POF17 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the RecA family. RAD51 subfamily.

RefSeq proteins (1): NP_005422* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013632	Rad51_C	Domain
IPR020588	RecA_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR030547	XRCC2	Family

Pfam: PF08423

UniProt features (51 total): sequence variant 25, strand 11, helix 10, turn 3, chain 1, modified residue 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
8OUZ	ELECTRON MICROSCOPY	2.2
8FAZ	ELECTRON MICROSCOPY	2.3
9SVY	ELECTRON MICROSCOPY	2.6
9Q29	ELECTRON MICROSCOPY	2.61
9Q2A	ELECTRON MICROSCOPY	2.67
9SVX	ELECTRON MICROSCOPY	2.7
9Q23	ELECTRON MICROSCOPY	2.84
9Q28	ELECTRON MICROSCOPY	2.84
9ZZR	ELECTRON MICROSCOPY	2.95
9SW0	ELECTRON MICROSCOPY	3
8GBJ	ELECTRON MICROSCOPY	3.11
9ON2	ELECTRON MICROSCOPY	3.16
9Q2B	ELECTRON MICROSCOPY	3.2
9Q25	ELECTRON MICROSCOPY	3.24
8OUY	ELECTRON MICROSCOPY	3.4
9OMZ	ELECTRON MICROSCOPY	3.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43543-F1	87.57	0.68

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 (1): 10

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
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-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-9709603	Impaired BRCA2 binding to PALB2

MSigDB gene sets: 469 (showing top): GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT, TGCGCANK_UNKNOWN, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_GROWTH, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, KAUFFMANN_DNA_REPAIR_GENES, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, KEGG_HOMOLOGOUS_RECOMBINATION, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_ANTERIOR_POSTERIOR_PATTERN_SPECIFICATION

GO Biological Process (17): mitotic cell cycle (GO:0000278), double-strand break repair via homologous recombination (GO:0000724), in utero embryonic development (GO:0001701), somitogenesis (GO:0001756), DNA repair (GO:0006281), centrosome cycle (GO:0007098), response to X-ray (GO:0010165), response to gamma radiation (GO:0010332), neurogenesis (GO:0022008), multicellular organism growth (GO:0035264), DNA strand invasion (GO:0042148), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of neurogenesis (GO:0050769), meiotic cell cycle (GO:0051321), regulation of fibroblast apoptotic process (GO:2000269), DNA recombination (GO:0006310), DNA damage response (GO:0006974)

GO Molecular Function (5): DNA binding (GO:0003677), ATP binding (GO:0005524), ATP-dependent DNA damage sensor activity (GO:0140664), four-way junction DNA binding (GO:0000400), protein binding (GO:0005515)

GO Cellular Component (7): nucleoplasm (GO:0005654), replication fork (GO:0005657), centrosome (GO:0005813), Rad51B-Rad51C-Rad51D-XRCC2 complex (GO:0033063), nucleus (GO:0005634), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-7 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	3
cellular anatomical structure	3
cell cycle	2
chordate embryonic development	2
response to ionizing radiation	2
mitotic nuclear division	1
recombinational repair	1
double-strand break repair	1
anterior/posterior pattern specification	1
segmentation	1
anatomical structure formation involved in morphogenesis	1
somite development	1
DNA damage response	1
cell cycle process	1
microtubule organizing center organization	1
nervous system development	1
cell differentiation	1
multicellular organismal process	1
developmental growth	1
DNA recombination	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
positive regulation of cell development	1
neurogenesis	1
regulation of neurogenesis	1
positive regulation of nervous system development	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
regulation of apoptotic process	1
fibroblast apoptotic process	1
cellular response to stress	1
nucleic acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ATP-dependent activity, acting on DNA	1
DNA damage sensor activity	1
DNA secondary structure binding	1
binding	1

Protein interactions and networks

STRING

1161 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XRCC2	K7EN88	K7EN88	999
XRCC2	RAD51D	O75771	999
XRCC2	XRCC3	O43542	996
XRCC2	RAD51B	O15315	990
XRCC2	RAD51C	O43502	989
XRCC2	BRCA2	P51587	960
XRCC2	BRCA1	P38398	898
XRCC2	RAD51	Q06609	866
XRCC2	FANCG	O15287	831
XRCC2	MRE11	P49959	811
XRCC2	BARD1	Q99728	774
XRCC2	XRCC1	P18887	748
XRCC2	PMS2	P54278	743
XRCC2	CHEK2	O96017	740
XRCC2	FANCD2	Q9BXW9	733

IntAct

71 interactions, top by confidence:

A	B	Type	Score
RAD51D	XRCC2	psi-mi:“MI:0915”(physical association)	0.980
XRCC2	RAD51D	psi-mi:“MI:0915”(physical association)	0.980
XRCC2	RAD51D	psi-mi:“MI:0403”(colocalization)	0.980
XRCC2	RAD51D	psi-mi:“MI:0407”(direct interaction)	0.980
RAD51D	XRCC2	psi-mi:“MI:0407”(direct interaction)	0.980

BioGRID (82): XRCC2 (Two-hybrid), XRCC2 (Two-hybrid), RAD51C (Affinity Capture-MS), RAD51B (Affinity Capture-MS), RAD51D (Affinity Capture-MS), XRCC2 (Affinity Capture-MS), XRCC2 (Affinity Capture-MS), XRCC2 (Affinity Capture-MS), XRCC2 (Two-hybrid), RAD51D (Two-hybrid), RAD51D (Two-hybrid), XRCC2 (Two-hybrid), XRCC2 (Affinity Capture-MS), RAD51D (Affinity Capture-MS), XRCC2 (Affinity Capture-MS)

ESM2 similar proteins: A2Y8B9, A7LFZ6, B5X561, C0LT23, F4K1G2, F4K2M8, F4KFT7, O43543, O82387, P84634, Q0DV28, Q10HL3, Q15KI9, Q4L235, Q58CU3, Q5R4D2, Q5RG49, Q5SNL7, Q5VS72, Q5W9E7, Q5Z856, Q682D3, Q69LX2, Q6AXL5, Q6E7H0, Q6P2P2, Q6TAS3, Q6USK2, Q7XD96, Q80WC9, Q84ND9, Q8BZT9, Q8H4D4, Q8L5Z4, Q8L870, Q8LPN3, Q8RWD9, Q8S8F2, Q8W032, Q8W4K1

Diamond homologs: A6VJS2, B6YXT4, C5A2F7, O15315, O29269, O35719, O43543, O57859, P25301, P25453, P50265, P81415, P95547, Q27297, Q2NHD1, Q57702, Q74MX9, Q8GXF0, Q99133, Q9CX47, Q9SK02, Q9V2F6, Q2NE95, O74036, Q9V233

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 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.

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair via homologous recombination	5	39.0×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	15
Uncertain significance	541
Likely benign	216
Benign	16

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
2625105	NM_005431.2(XRCC2):c.190del (p.Arg64fs)	Pathogenic
3471451	NM_005431.2(XRCC2):c.316_319del (p.Glu105_Glu106insTer)	Pathogenic
1256050	NM_005431.2(XRCC2):c.347_350del (p.Phe116fs)	Likely pathogenic
1734845	NM_005431.2(XRCC2):c.377T>G (p.Leu126Ter)	Likely pathogenic
1743849	NM_005431.2(XRCC2):c.488dup (p.Glu164fs)	Likely pathogenic
1751566	NM_005431.2(XRCC2):c.609del (p.Ser204fs)	Likely pathogenic
1777469	NM_005431.2(XRCC2):c.166_167del (p.Glu56fs)	Likely pathogenic
1779551	NM_005431.2(XRCC2):c.175del (p.Tyr59fs)	Likely pathogenic
1790724	NM_005431.2(XRCC2):c.240_243del (p.Phe80fs)	Likely pathogenic
1793662	NM_005431.2(XRCC2):c.26_27del (p.Glu9fs)	Likely pathogenic
1798671	NM_005431.2(XRCC2):c.2T>C (p.Met1Thr)	Likely pathogenic
2562726	NM_005431.2(XRCC2):c.395C>A (p.Ser132Ter)	Likely pathogenic
3224683	NM_005431.2(XRCC2):c.539T>G (p.Leu180Ter)	Likely pathogenic
4845630	NM_005431.2(XRCC2):c.678T>A (p.Tyr226Ter)	Likely pathogenic
818627	NM_005431.2(XRCC2):c.122-1G>T	Likely pathogenic
825274	NM_005431.2(XRCC2):c.490_491del (p.Glu164fs)	Likely pathogenic
929638	NM_005431.2(XRCC2):c.350del (p.Leu117fs)	Likely pathogenic

SpliceAI

909 predictions. Top by Δscore:

Variant	Effect	Δscore
7:152660784:T:TC	acceptor_gain	1.0000
7:152676036:CTCA:C	donor_loss	1.0000
7:152676038:CACC:C	donor_loss	1.0000
7:152676039:ACC:A	donor_loss	1.0000
7:152676056:AGC:A	donor_gain	1.0000
7:152652624:CTTGA:C	donor_gain	0.9900
7:152652625:TTGAT:T	donor_gain	0.9900
7:152652626:TGATT:T	donor_gain	0.9900
7:152652636:T:A	donor_gain	0.9900
7:152660784:T:C	acceptor_gain	0.9900
7:152669262:T:TA	donor_gain	0.9900
7:152669286:T:TA	donor_gain	0.9900
7:152676039:A:AC	donor_gain	0.9900
7:152676040:C:CC	donor_gain	0.9900
7:152676040:CCT:C	donor_gain	0.9900
7:152676056:AG:A	donor_gain	0.9900
7:152676057:G:C	donor_gain	0.9900
7:152652623:A:AC	donor_gain	0.9800
7:152652624:C:CC	donor_gain	0.9800
7:152660786:A:C	acceptor_gain	0.9800
7:152669259:AGGT:A	donor_gain	0.9800
7:152669289:TTCA:T	donor_gain	0.9800
7:152669298:T:TA	donor_gain	0.9800
7:152676111:A:C	donor_gain	0.9800
7:152669279:T:C	donor_gain	0.9700
7:152676072:C:CT	donor_gain	0.9700
7:152676073:T:TT	donor_gain	0.9700
7:152648903:CGT:C	acceptor_gain	0.9600
7:152676115:T:A	donor_gain	0.9600
7:152649359:ATCAC:A	acceptor_loss	0.9400

AlphaMissense

1840 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:152648794:A:G	W231R	0.992
7:152648794:A:T	W231R	0.992
7:152649324:T:A	K54I	0.992
7:152649327:C:T	G53E	0.990
7:152649321:G:A	T55I	0.987
7:152649213:C:G	R91P	0.986
7:152649342:C:T	G48D	0.986
7:152649323:T:A	K54N	0.985
7:152649323:T:G	K54N	0.985
7:152648792:C:A	W231C	0.982
7:152648792:C:G	W231C	0.982
7:152649210:A:G	L92P	0.982
7:152649343:C:G	G48R	0.981
7:152649023:A:C	F154L	0.980
7:152649023:A:T	F154L	0.980
7:152649025:A:G	F154L	0.980
7:152649035:G:C	S150R	0.980
7:152649035:G:T	S150R	0.980
7:152649037:T:G	S150R	0.980
7:152649288:A:T	I66K	0.980
7:152649303:A:G	L61P	0.980
7:152649324:T:G	K54T	0.980
7:152649009:C:G	R159P	0.977
7:152649198:A:G	L96P	0.977
7:152649327:C:A	G53V	0.976
7:152649116:G:C	S123R	0.975
7:152649116:G:T	S123R	0.975
7:152649118:T:G	S123R	0.975
7:152649292:A:G	C65R	0.975
7:152648655:A:T	V277D	0.973

dbSNP variants (sampled 300 via entrez): RS1000096058 (7:152650908 A>G), RS1000120005 (7:152671862 G>A), RS1000123683 (7:152671945 GT>G), RS1000193002 (7:152664966 G>A), RS1000245621 (7:152665293 G>A), RS1000336890 (7:152664449 C>A), RS1000497285 (7:152672270 G>GTT), RS1000501867 (7:152651969 G>A), RS1000529044 (7:152646567 C>T), RS1000645093 (7:152646336 T>A), RS1000708287 (7:152677768 A>G), RS1000720487 (7:152659607 C>T), RS1000890997 (7:152676831 CAAAAA>C,CA,CAA,CAAA,CAAAA,CAAAAAA,CAAAAAAA), RS1000950309 (7:152665933 G>T), RS1001010394 (7:152645581 A>G)

Disease associations

OMIM: gene MIM:600375 | disease phenotypes: MIM:261740, MIM:617247, MIM:619145, MIM:619146, MIM:114500, MIM:616541

GenCC curated gene-disease

Disease	Classification	Inheritance
Fanconi anemia complementation group U	Moderate	Autosomal recessive
male infertility with azoospermia or oligozoospermia due to single gene mutation	Supportive	Autosomal dominant
Fanconi anemia	Supportive	Autosomal recessive
spermatogenic failure 50	Limited	Unknown
premature ovarian failure 17	Limited	Unknown
breast cancer	Disputed Evidence	Autosomal dominant
familial ovarian cancer	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
Fanconi anemia complementation group U	Limited	AR
hereditary breast carcinoma	Refuted	AD
familial ovarian cancer	No Known Disease Relationship	AD

Mondo (15): hereditary neoplastic syndrome (MONDO:0015356), lethal congenital glycogen storage disease of heart (MONDO:0009867), breast carcinoma (MONDO:0004989), Fanconi anemia complementation group U (MONDO:0014987), spermatogenic failure 50 (MONDO:0030869), premature ovarian failure 17 (MONDO:0030870), malignant colon neoplasm (MONDO:0021063), colorectal cancer (MONDO:0005575), cancer of unknown primary site (MONDO:0858997), short stature, microcephaly, and endocrine dysfunction (MONDO:0014686), hereditary breast ovarian cancer syndrome (MONDO:0003582), breast cancer (MONDO:0007254), familial ovarian cancer (MONDO:0016248), (MONDO:0018393), Fanconi anemia (MONDO:0019391)

Orphanet (6): Inherited cancer-predisposing syndrome (Orphanet:140162), Fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease (Orphanet:439854), Cancer of unknown primary site (Orphanet:631251), Microcephalic primordial dwarfism-insulin resistance syndrome (Orphanet:436182), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

131 total (30 of 131 shown, HPO-id order):

HPO	Term
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:0000086	Ectopic kidney
HP:0000118	Phenotypic abnormality
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
HP:0000486	Strabismus

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001838_7	Palmitic acid (16:0) levels	4.000000e-06
GCST003098_18	Diabetic kidney disease	2.000000e-07
GCST004599_61	Mean platelet volume	4.000000e-11
GCST90002395_706	Mean platelet volume	3.000000e-13
GCST90002395_707	Mean platelet volume	1.000000e-35

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D005199	Fanconi Anemia	C15.378.050.085.080.280; C15.378.190.223.500.500.280; C16.320.077.280; C18.452.284.280
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
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
C564888	Glycogen Storage Disease of Heart, Lethal Congenital (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	3
bisphenol A	decreases expression, decreases methylation	2
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression, increases expression	2
Air Pollutants	increases expression, affects cotreatment, increases abundance, increases oxidation	2
Cannabidiol	decreases expression	2
Endosulfan	affects cotreatment, increases expression, decreases expression	2
Oxygen	decreases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment	2
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
pradimicin-IRD	decreases expression, affects expression, affects response to substance	1
myristicin	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
4-biphenylamine	decreases expression	1
glycidyl methacrylate	decreases expression	1
VX-agent	increases expression	1
terbufos	decreases expression, affects cotreatment, increases expression	1
bromoacetate	decreases expression	1
sodium arsenite	increases expression	1
zinc chromate	decreases expression, increases abundance	1
fludarabine	affects cotreatment, decreases expression	1
manganese chloride	increases abundance, increases expression	1
coumarin	increases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
chromium hexavalent ion	decreases expression, increases abundance	1
cylindrospermopsin	increases expression	1
2-palmitoylglycerol	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
LAQ824	affects cotreatment, decreases expression	1

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_VR84	U2OS#18-XRCC2-5E	Cancer cell line	Female
CVCL_VR85	U2OS#18-XRCC2-5E/X2+	Cancer cell line	Female
CVCL_XX04	HEK293-DR-GFP-XRCC2-13	Transformed cell line	Female
CVCL_XX09	HEK293-DR-GFP-XRCC2-13/X2+	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT00638599	PHASE4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	PHASE4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	PHASE4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	PHASE4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	PHASE4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer
NCT00754767	PHASE4	TERMINATED	L-Carnitine L-Tartrate in Preventing Peripheral Neuropathy Caused By Chemotherapy in Women With Metastatic Breast Cancer