XRCC2

protein-coding

X-ray repair cross complementing 2, the group of FA complementation groups

Gene summary

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. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005431.2

Inheritance

AR, AD

ClinVar variants

P:32U:523B:213

Top phenotype

Fanconi anemia, complementation group U

gnomAD constraint

pLI —, LoF o/e 0.83

Max pathogenic AF

—

Genomic locus

chr7:152,644,776-152,676,193

External References & Databases

Ensembl (ENSG00000196584)

Transcript & Mutation Effects

hg38 • Region Span ~31.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fanconi anemia complementation group UMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014987

Submitter: PanelApp Australia

Fanconi anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

hereditary breast carcinomaNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

XRCC2 (X-ray repair cross-complementary group 2) gene is a member of the family of RAD51-related proteins that participate in homologous recombination (HR). It forms the BCDX2 complex with RAD51B, RAD51C, and RAD51D, and is required for HR repair. There are 3 exons that make up the protein, and there is a G to A transition located in exon 3 that results in a substitution of histidine (His) by arginine (Arg), known as R188H (Arg188His, rs3218536). This polymorphism has been widely investigated to explore its potential impact on cancer susceptibility. Biallelic XRCC2 mutations are associated with Fanconi anemia, complementation group U, Premature ovarian failure, and Spermatogenic failure. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we only focus on hereditary breast cancer (refute the association with breast cancer) in this curation. Evidence refuting this gene-disease relationship includes case-control data, while experimental data supports the role of XRCC2 in DNA repair. **Summary of Case-Control Data: 0 POINTS** This gene-disease relationship has been studied in at least 11 case-control studies at the aggregate variant level. In 2021, two large case-control studies [CARRIERS (PMID: 33471974) and BCAC (PMID: 33471991); both with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in XRCC2 and breast cancer. Nine other case-control studies, with smaller populations ranging from 150 to 13078, likewise, did not show any association of LOF variants with breast cancer. Various populations were involved, including Pakistani (PMID: 25556451), South Indian (PMID: 35061678), Tanzania (PMID: 35691022), British (PMID: 28779002), Ethnic Slavs (PMID: 31173646), Chinese (PMID: 4642895), Cyprus (PMID: 16485136), and US American (PMID: 14578164 and 18188695). **Summary of Experimental Data: 2 POINTS** While case control studies did not support the gene-disease association, two experimental studies showing the role of XRCC2 in heightened sensitivity to ionizing radiation and particularly to the DNA cross-linking chemical mitomycin C (0.5 point for each study, PMID: 10422536, 11025669). Another study reported that in chicken cells, RAD51 paralog mutant cells (like XRCC2), exhibited that same pattern of hypermutation (0.5 point, PMID:15657438). Lastly, knock-out mice exhibited chromosomal instability and embryonic lethality (0.5 point, PMID:11118202). **Overall Summary:** In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between XRCC2 and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 5/10//2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 2/17/2023 (SOP Version 9).

Fanconi anemia complementation group UMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014987

Submitter: Ambry Genetics

male infertility with azoospermia or oligozoospermia due to single gene mutationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018393

Submitter: Orphanet

spermatogenic failure 50LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030869

Submitter: Labcorp Genetics (formerly Invitae)

premature ovarian failure 17LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030870

Submitter: Labcorp Genetics (formerly Invitae)

Fanconi anemia complementation group ULIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014987

Submitter: Labcorp Genetics (formerly Invitae)

familial ovarian cancerNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0016248

Submitter: ClinGen

Fanconi anemia complementation group ULIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014987

Submitter: ClinGen

*XRCC2* (X-ray repair cross-complementary group 2) gene is a member of the family of RAD51-related proteins that participate in homologous recombination (HR). It forms the BCDX2 complex with RAD51B, RAD51C, and RAD51D, and is required for HR repair. XRCC2 was first reported in relation to autosomal recessive Fanconi anemia, complementation group U in 2012 (Shamseldin HE, et al., PMID: 22232082). Fanconi anemia is a rare hereditary disease characterized by genomic instability, developmental abnormalities, bone marrow failure and cancer predisposition, mainly leukemia and solid tumors. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split autosomal dominant hereditary breast cancer into separate curations due to phenotypic variability and different inheritance patterns. Therefore, this curation solely focuses on autosomal recessive FA-U. The mechanism of pathogenicity is loss of function. One homozygous nonsense variant has been reported in one proband in two publications (3 Points, PMIDs: 22232082, 27208205) is included in this curation. This gene-disease relationship is also supported by experimental evidence (2 Points). in vitro functional assays (PMID: 27208205) showed that cells (900677A) from a previously identified patient with biallelic mutation of XRCC2 display cellular hypersensitivity to DNA interstrand crosslinking agent or IR, similar to cells with deficiencies with other well-known FA genes. Importantly, these cellular phenotypes can be rescued by expression of wildtype XRCC2. In summary, there is limited evidence supporting the relationship between XRCC2 and autosomal recessive inheritance Fanconi anemia, complementation group U . This classification was approved by the ClinGen Hereditary Cancer GCEP on the meeting date October 27, 2023 (SOP Version 9).

breast cancerNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: Ambry Genetics

Fanconi anemia complementation group ULIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014987

Submitter: LiferaOmics

ClinGen XRCC2–related Fanconi anemia complementation group U (AR) – Limited – Approval: 2023 ClinGen Evidence Breakdown Genetic Evidence = 3.0 point Based on: • PMID: 22232082 (Shamseldin et al., 2012) • PMID: 27208205 (Park et al., 2016 – same proband follow-up; no additional genetic points) Single homozygous nonsense proband (p.Arg215Ter); consanguineous family (−0.5 applied). Experimental Evidence = 2.0 points Based on: • PMID: 27208205 (patient-cell functional alteration: hypersensitivity to DNA crosslinking agents; chromosome instability; RAD51 focus defects) • PMID: 27208205 (rescue of cellular phenotype with wild-type XRCC2 expression) ClinGen Total = 5.0 (3.0 genetic + 2.0 experimental) Genetic Evidence – Our Case Family 2 – one proband. Case-level (AR predicted null default; homozygous; consanguineous = −0.5 applied) = 1.0; Segregation = 0; Case-control = 0 Family 2 total = 1.0 Our Case Total = 1.0 / 12 Updated Total Genetic Evidence (ClinGen + Our Case) ClinGen genetic evidence: 3.0 Our additional case: +1.0 Updated genetic total = 4.0 / 12 Experimental Evidence (unchanged from ClinGen) ClinGen experimental evidence = 2.0 Our additional experimental evidence = 0 Updated Overall Score Genetic evidence = 4.0 Experimental evidence = 2.0 Updated total = 6.0

Clinical Genomic Database (CGD)

Fanconi anemia, complementation group UAR

Manifestation: Cardiovascular; Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Fanconi anemia can involve congenital cardiac (and other) anomalies, and awareness may allow early management

Comments: In individuals with Fanconi anemia, complementation group U, hematologic or oncologic manifestations have not been described

Refs: 22232082; 27208205; 30042186; 30489636

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to XRCC2 variants in ClinVar

13 Conditions Cataloged

Hereditary cancer-predisposing syndromeTotal: 687

not providedTotal: 368

not specifiedTotal: 57

Fanconi anemia complementation group UTotal: 34

XRCC2-related disorderTotal: 17

Premature ovarian failure 17Total: 13

Spermatogenic failure 50Total: 12

Hereditary breast ovarian cancer syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005431.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	173 clinvar		177
missense			474 clinvar	40 clinvar		514
nonsense		9 clinvar	13 clinvar			22
start loss		1 clinvar	1 clinvar			2
frameshift	2 clinvar	17 clinvar	28 clinvar			47
splice donor/acceptor (+/-2bp)		3 clinvar	3 clinvar			6
Total	2	30	523	213	0	768

Highest pathogenic variant AF is 0.00006320431

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005431.2	RefSeq	NP_005422.1	3	MANE Select
ENST00000359321.2	Ensembl	ENSP00000352271.1	3	MANE Select
ENST00000698506.1	Ensembl	ENSP00000513758.1	1	Standard
ENST00001013524.1	Ensembl	ENSP00000683341.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Homologous recombination - Homo sapiens (human)
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
DNA Repair
DNA Double-Strand Break Repair
Homology Directed Repair

Biological Process

mitotic cell cycle
double-strand break repair via homologous recombination
in utero embryonic development
somitogenesis
DNA repair

Molecular Function

four-way junction DNA binding
protein binding
ATP binding
DNA-dependent ATPase activity

Cellular Component

nucleoplasm
replication fork
cytoplasm
centrosome
Rad51B-Rad51C-Rad51D-XRCC2 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359321
Coding exons: 3
Length: 31387
Individuals with no LoFs: 125665
Homozygous LoFs: 0
Heterozygous LoFs: 82
Defined: 125747
p: 0.000326

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.127	152	148	1.03	0.00000740	1836
Missense (PolyPhen)		58	57.447	1.0096		731
Synonymous	1.09	43	53.1	0.810	0.00000250	534
Loss of Function	0.578	11	13.3	0.829	9.10e-7	141

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.000056	0.000054	rare
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.00043	0.00043	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA, thought to repair chromosomal fragmentation, translocations and deletions. Part of the Rad21 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. {ECO:0000269|PubMed:11751635, ECO:0000269|PubMed:11834724, ECO:0000269|PubMed:21276791, ECO:0000269|PubMed:23149936, ECO:0000269|PubMed:27233470}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:22232082}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.223

Intolerance Scores

LoFtool: 0.862
RVIS EVS: 0.02
RVIS percentile EVS: 55.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.684

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium