Breast-ovarian cancer, familial, susceptibility to, 4

Summary

Breast-ovarian cancer, familial, susceptibility to, 4 (MONDO:0013669) is a cancer caused by RAD51D (GenCC Strong), with 3 cohort genes (1 CIViC-evidence somatic driver; 1,654 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: RAD51D (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1,654

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	breast-ovarian cancer, familial, susceptibility to, 4
Mondo ID	MONDO:0013669
OMIM	614291
UMLS	C3280345
MedGen	481975
Is cancer (heuristic)	yes

Also known as: breast-ovarian cancer, familial, susceptibility to, 4 · breast-ovarian cancer, familial, susceptibility to, type 4 · BROVCA4 · hereditary breast ovarian cancer syndrome caused by mutation in RAD51D · RAD51D hereditary breast ovarian cancer syndrome

Data availability: 1,654 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › breast-ovarian cancer, familial, susceptibility to › breast-ovarian cancer, familial, susceptibility to, 4

Related subtypes (4): breast-ovarian cancer, familial, susceptibility to, 1, breast-ovarian cancer, familial, susceptibility to, 2, breast-ovarian cancer, familial, susceptibility to, 3, breast-ovarian cancer, familial, susceptibility to, 5

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

235 uncertain significance, 108 likely benign, 94 benign/likely benign, 83 conflicting classifications of pathogenicity, 44 pathogenic, 17 likely pathogenic, 16 pathogenic/likely pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068166	NM_002878.4(RAD51D):c.886del (p.Ala296fs)	RAD51D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072692	NC_000017.10:g.(?33446541)(33446632_?)del	RAD51D	Pathogenic	criteria provided, single submitter
1072693	NC_000017.10:g.(?33443985)(33446632_?)del	RAD51D	Pathogenic	criteria provided, single submitter
1072694	NC_000017.10:g.(?33427972)(33430573_?)del	RAD51D	Pathogenic	criteria provided, single submitter
1074165	NM_002878.4(RAD51D):c.167dup (p.Leu57fs)	RAD51D	Pathogenic	criteria provided, single submitter
1074527	NM_002878.4(RAD51D):c.502C>T (p.Gln168Ter)	RAD51D	Pathogenic	criteria provided, multiple submitters, no conflicts
1075870	NM_002878.4(RAD51D):c.256del (p.Ile86fs)	RAD51D	Pathogenic	criteria provided, single submitter
1098875	NM_002878.4(RAD51D):c.754del (p.Thr252fs)	RAD51D	Pathogenic	criteria provided, single submitter
1098882	NM_002878.4(RAD51D):c.144+1G>T	RAD51D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098883	NM_002878.4(RAD51D):c.24_27del (p.Cys9fs)	RAD51D	Pathogenic	criteria provided, single submitter
1177652	NM_002878.4:c.82_577-1del	RAD51D	Pathogenic	criteria provided, single submitter
1177657	NM_002878.4:c.1_263del	RAD51D	Pathogenic	criteria provided, single submitter
1177659	NM_002878.4(RAD51D):c.146_263+1del	RAD51D	Pathogenic	criteria provided, single submitter
1177660	NM_002878.4:c.740_987del	RAD51D	Pathogenic	criteria provided, single submitter
1177662	NM_001142571.1:c.963_1047del	RAD51D	Pathogenic	criteria provided, single submitter
1177663	NM_002878.4:c.1_987del	RAD51D	Pathogenic	criteria provided, single submitter
127893	NM_002878.4(RAD51D):c.694C>T (p.Arg232Ter)	RAD51D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
141143	NM_002878.4(RAD51D):c.649_655delinsTGAGGTT (p.Gly217_Gln219delinsTer)	RAD51D	Pathogenic	criteria provided, multiple submitters, no conflicts
141452	NM_002878.4(RAD51D):c.451C>T (p.Gln151Ter)	RAD51D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142754	NM_002878.4(RAD51D):c.547C>T (p.Gln183Ter)	RAD51D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
142811	NM_002878.4(RAD51D):c.140_141insAA (p.Tyr47Ter)	RAD51D	Pathogenic	criteria provided, multiple submitters, no conflicts
1453810	NM_002878.4(RAD51D):c.482dup (p.Glu162fs)	RAD51D	Pathogenic	criteria provided, multiple submitters, no conflicts
1458065	NM_002878.4(RAD51D):c.486del (p.Ala163fs)	RAD51D	Pathogenic	criteria provided, multiple submitters, no conflicts
1472197	NM_002878.4(RAD51D):c.576+2T>C	RAD51D	Pathogenic	criteria provided, single submitter
1506962	NM_002878.4(RAD51D):c.694_697dup (p.Glu233fs)	RAD51D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1713232	NM_002878.4(RAD51D):c.896_*505del597insT (p.Ser299fs)	RAD51D	Pathogenic	criteria provided, single submitter
1735878	NM_002878.4(RAD51D):c.388C>T (p.Gln130Ter)	RAD51D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1739847	NM_002878.4(RAD51D):c.433del (p.Arg145fs)	RAD51D	Pathogenic	criteria provided, multiple submitters, no conflicts
1748797	NM_002878.4(RAD51D):c.564_568delinsA (p.Val189fs)	RAD51D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1795803	NM_002878.4(RAD51D):c.277_280del (p.Leu93fs)	RAD51D	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
RAD51D			CIViC #4765

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RAD51D	Strong	Autosomal dominant	breast-ovarian cancer, familial, susceptibility to, 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAD51D	Orphanet:1331	Familial prostate cancer
RAD51D	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAD51D	HGNC:9823	ENSG00000185379	O75771	DNA repair protein RAD51 homolog 4	gencc,clinvar
FNDC8	HGNC:25286	ENSG00000073598	Q8TC99	Fibronectin type III domain-containing protein 8	clinvar
FMN1	HGNC:3768	ENSG00000248905	Q68DA7	Formin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAD51D	DNA repair protein RAD51 homolog 4	Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents.
FMN1	Formin-1	Plays a role in the formation of adherens junction and the polymerization of linear actin cables.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAD51D	Other/Unknown	no		AAA+_ATPase, Rad51_C, DNA_recomb/repair_RecA-like
FNDC8	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, FN3_sf
FMN1	Other/Unknown	no		Formin_Cappuccino_subfam, FH2_Formin, FH2_Formin_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ cell	1
oocyte	1
sperm	1
left testis	1
right testis	1
testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAD51D	187	ubiquitous	yes	sperm, male germ cell, oocyte
FNDC8	56	tissue_specific	marker	left testis, right testis, testis
FMN1	171	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAD51D	3,089
FMN1	1,605
FNDC8	170

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAD51D	O75771	17

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FNDC8	Q8TC99	60.64
FMN1	Q68DA7	55.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Impaired BRCA2 binding to PALB2	1	456.8×	0.004	RAD51D
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	423.0×	0.004	RAD51D
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	423.0×	0.004	RAD51D
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	423.0×	0.004	RAD51D
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	393.8×	0.004	RAD51D
Homologous DNA Pairing and Strand Exchange	1	380.7×	0.004	RAD51D
Resolution of D-loop Structures through Holliday Junction Intermediates	1	300.5×	0.005	RAD51D
Presynaptic phase of homologous DNA pairing and strand exchange	1	271.9×	0.005	RAD51D
HDR through Homologous Recombination (HRR)	1	190.3×	0.006	RAD51D
TP53 Regulates Transcription of DNA Repair Genes	1	181.3×	0.006	RAD51D

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA strand invasion	1	2106.5×	0.004	RAD51D
actin nucleation	1	936.2×	0.004	FMN1
telomere maintenance via recombination	1	766.0×	0.004	RAD51D
reciprocal meiotic recombination	1	280.9×	0.009	RAD51D
interstrand cross-link repair	1	216.1×	0.009	RAD51D
telomere maintenance	1	133.8×	0.012	RAD51D
double-strand break repair via homologous recombination	1	78.0×	0.018	RAD51D
actin cytoskeleton organization	1	39.6×	0.030	FMN1
regulation of cell cycle	1	37.3×	0.030	RAD51D
DNA repair	1	31.9×	0.031	RAD51D

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAD51D	0	0
FNDC8	0	0
FMN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Drug repurposing candidates

0 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	FNDC8
E	Difficult family or no structure, no drug	2	RAD51D, FMN1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RAD51D	0	—
FNDC8	0	—
FMN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.