RAD51D

protein-coding

RAD51 paralog D

Gene summary

The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]

Previous symbols:

RAD51L3

MANE transcript

NM_002878.4

Inheritance

ClinVar variants

P:280U:842B:444

Top phenotype

Breast-ovarian cancer, familial, susceptibility to, 4

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr17:35,092,221-35,121,522

External References & Databases

Ensembl (ENSG00000185379)

Transcript & Mutation Effects

hg38 • Region Span ~29.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

breast-ovarian cancer, familial, susceptibility to, 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013669

Submitter: Ambry Genetics

breast-ovarian cancer, familial, susceptibility to, 4LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013669

Submitter: PanelApp Australia

hereditary breast ovarian cancer syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0003582

Submitter: Orphanet

breast-ovarian cancer, familial, susceptibility to, 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013669

Submitter: Genomics England PanelApp

RAD51D-related cancer predispositionDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700274

Submitter: ClinGen

The protein encoded by RAD51D gene is a member of the RAD51 protein family. The protein complex formed with RAD51D protein has been shown to catalyze homologous pairing between single- and double-stranded DNA and is thought to play a role in the early stage of recombinational repair of DNA. RAD51D has been linked to autosomal dominant RAD51D-related cancer predisposition which includes familial ovarian cancer, triple negative breast cancer and ER negative breast cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern among the different cancer predispositions. Therefore, these phenotypes have been lumped into this RAD51D-related cancer predisposition curation. This gene-disease relationship has been studied in at least eight case-control studies at the aggregate variant level. These case-control studies suggested significantly increased risk for ovarian cancer in monoallelic RAD51D variant carriers compared to controls (12 points) (PMIDs: 26261251, 26720728, 30099541, 31341520, 32091585, 33471991, 35084436, 35172496). This gene-disease relationship is also supported by experimental evidence including functional alteration and protein interaction studies (1.5 points; PMIDs: 10749867, 11751635, 27924006). RAD51D-deficient cells had a significantly higher frequency of spontaneous double-strand break. In addition, these cells had a severely reduced capacity for homologous recombination-mediated DNA repair. Yeast two-hybrid and co-immunoprecipitation assays also revealed RAD51D directly interacts with RAD51C and forms a protein complex. In summary, RAD51D is definitively associated with RAD51D-related cancer predisposition (MONDO:0700274). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated as definitive for familial ovarian cancer on 10/11/2017 and as limited for hereditary breast carcinoma on 11/08/2017 by the Breast/Ovarian Cancer GCEP. This lumped re-curation as definitive was approved by the ClinGen Hereditary Cancer GCEP on 03/22/2024 (SOP Version 10).

breast-ovarian cancer, familial, susceptibility to, 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013669

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Breast-ovarian cancer, familial, susceptibility to, 4AD

Manifestation: Oncologic

Intervention: Oncologic

Rationale: Surveillance (similar to that described for individuals with variants in BRCA1 or BRCA2) related to breast or ovarian cancer may allow early diagnosis and treatment of neoplasms (eg, ovarian tumors), which may reduce morbidity and mortality; Specific, targeted therapies may be available

Refs: 21822267; 23300655; 23372765

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAD51D variants in ClinVar

35 Conditions Cataloged

Breast-ovarian cancer, familial, susceptibility to, 4Total: 1601

Hereditary cancer-predisposing syndromeTotal: 1303

not providedTotal: 381

not specifiedTotal: 226

Hereditary breast ovarian cancer syndromeTotal: 103

RAD51D-related disorderTotal: 84

Familial ovarian cancerTotal: 34

Breast and/or ovarian cancerTotal: 33

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002878.4. 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		3 clinvar	13 clinvar	339 clinvar	39 clinvar	394
missense		5 clinvar	800 clinvar	63 clinvar	3 clinvar	871
nonsense	31 clinvar	20 clinvar	8 clinvar			59
start loss		9 clinvar	1 clinvar			10
frameshift	81 clinvar	59 clinvar	10 clinvar			150
splice donor/acceptor (+/-2bp)	6 clinvar	66 clinvar	10 clinvar			82
Total	118	162	842	402	42	1566

Highest pathogenic variant AF is 0.000031598593

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002878.4	RefSeq	NP_002869.3	10	MANE Select
ENST00000345365.11	Ensembl	ENSP00000338790.6	10	MANE Select
NM_001142571.2	RefSeq	NP_001136043.1	10	Standard
NM_133629.3	RefSeq	NP_598332.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Homologous recombination - Homo sapiens (human)
TP53 Regulates Transcription of DNA Repair Genes
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
DNA Repair
Gene expression (Transcription)

Biological Process

telomere maintenance
double-strand break repair via homologous recombination
DNA repair
reciprocal meiotic recombination
interstrand cross-link repair

Molecular Function

four-way junction DNA binding
DNA binding
single-stranded DNA binding
protein binding
ATP binding

Cellular Component

chromosome, telomeric region
nuclear chromosome, telomeric region
nucleus
nucleoplasm
replication fork

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000590016
Coding exons: 10
Length: 21731
Individuals with no LoFs: 125695
Homozygous LoFs: 0
Heterozygous LoFs: 53
Defined: 125748
p: 0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.112	198	194	1.02	0.0000115	2194
Missense (PolyPhen)		60	57.789	1.0383		708
Synonymous	-0.0429	81	80.5	1.01	0.00000492	755
Loss of Function	0.820	16	20.0	0.802	0.00000123	199

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00070	0.00069	rare
East Asian	0.00087	0.00087	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00017	0.00015	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. Bind to single- stranded DNA (ssDNA) and has DNA-dependent ATPase activity. 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. Involved in telomere maintenance. The BCDX2 subcomplex XRCC2:RAD51D can stimulate Holliday junction resolution by BLM. {ECO:0000269|PubMed:10871607, ECO:0000269|PubMed:11751635, ECO:0000269|PubMed:11834724, ECO:0000269|PubMed:11842113, ECO:0000269|PubMed:12975363, ECO:0000269|PubMed:15109494, ECO:0000269|PubMed:23149936}.;

Intolerance Scores

RVIS EVS: 0.53
RVIS percentile EVS: 80.96

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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