FANCC

Summary

FANCC (FA complementation group C, HGNC:3584) is a protein-coding gene on chromosome 9q22.32, encoding Fanconi anemia group C protein (Q00597). DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function. In precision oncology, FANCC Loss-of-function confers sensitivity to Cisplatin + Melphalan + Chlorambucil + Mitomycin + Gemcitabine in Pancreatic Cancer (CIViC Level D).

The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C.

Source: NCBI Gene 2176 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fanconi anemia complementation group C (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 1,251 total — 82 pathogenic, 67 likely-pathogenic
• Phenotypes (HPO): 137
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000136

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3584
Approved symbol	FANCC
Name	FA complementation group C
Location	9q22.32
Locus type	gene with protein product
Status	Approved
Aliases	FAC, FA3
Ensembl gene	ENSG00000158169
Ensembl biotype	protein_coding
OMIM	613899
Entrez	2176

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 14 protein_coding, 11 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000289081, ENST00000375305, ENST00000433644, ENST00000433829, ENST00000464627, ENST00000464653, ENST00000474949, ENST00000477942, ENST00000480712, ENST00000490972, ENST00000493098, ENST00000636777, ENST00000647778, ENST00000647882, ENST00000648415, ENST00000649334, ENST00000649519, ENST00000649611, ENST00000649701, ENST00000649872, ENST00000650176, ENST00000696260, ENST00000696261, ENST00000696262, ENST00000696263, ENST00000863589, ENST00000863590, ENST00000863591, ENST00000863592, ENST00000919082

RefSeq mRNA: 3 — MANE Select: NM_000136 NM_000136, NM_001243743, NM_001243744

CCDS: CCDS35071, CCDS75861

Canonical transcript exons

ENST00000289081 — 15 exons

Exon	Start	End
ENSE00001037434	95107066	95107269
ENSE00001466652	95099054	95101850
ENSE00001466653	95317526	95317709
ENSE00001682659	95135346	95135502
ENSE00001758186	95149923	95150087
ENSE00001774158	95171079	95171143
ENSE00003474211	95117315	95117390
ENSE00003493147	95172037	95172147
ENSE00003516801	95240649	95240743
ENSE00003520968	95111463	95111637
ENSE00003537157	95125086	95125185
ENSE00003572018	95249127	95249369
ENSE00003596105	95247432	95247516
ENSE00003634487	95114629	95114710
ENSE00003666712	95126529	95126581

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 90.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.6086 / max 99.0512, expressed in 1660 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101549	7.0167	1615
101552	1.1470	643
101547	0.8407	306
101548	0.2902	132
101551	0.2868	174
101533	0.0273	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	90.66	gold quality
right lobe of liver	UBERON:0001114	88.14	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.08	gold quality
right testis	UBERON:0004534	85.80	gold quality
left testis	UBERON:0004533	85.63	gold quality
sural nerve	UBERON:0015488	85.62	gold quality
liver	UBERON:0002107	84.33	gold quality
testis	UBERON:0000473	84.21	gold quality
cerebellar hemisphere	UBERON:0002245	82.93	gold quality
cerebellar cortex	UBERON:0002129	82.81	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.74	gold quality
calcaneal tendon	UBERON:0003701	82.52	gold quality
ganglionic eminence	UBERON:0004023	82.37	gold quality
ventricular zone	UBERON:0003053	82.19	gold quality
endometrium epithelium	UBERON:0004811	82.09	silver quality
colonic epithelium	UBERON:0000397	81.71	gold quality
body of pancreas	UBERON:0001150	81.43	gold quality
cerebellum	UBERON:0002037	80.97	gold quality
secondary oocyte	CL:0000655	80.85	gold quality
descending thoracic aorta	UBERON:0002345	80.48	gold quality
mucosa of stomach	UBERON:0001199	80.07	gold quality
thoracic aorta	UBERON:0001515	79.82	gold quality
rectum	UBERON:0001052	79.81	gold quality
pancreas	UBERON:0001264	79.77	gold quality
ascending aorta	UBERON:0001496	79.75	gold quality
islet of Langerhans	UBERON:0000006	79.66	gold quality
aorta	UBERON:0000947	79.50	gold quality
ileal mucosa	UBERON:0000331	79.46	gold quality
popliteal artery	UBERON:0002250	79.44	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, TP53

miRNA regulators (miRDB)

53 targeting FANCC, 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-6873-3P	100.00	71.42	2626
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-3606-5P	99.31	69.67	1168
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 39)

• The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of this protein. (PMID:12239156)
• Hsp70 requires the cooperation of FANCC to suppress PKR activity and support survival of hematopoietic cells and FANCC does not require the multimeric Fanconi anemia complex to exert this function (PMID:12397061)
• Fancc-/- phenotypically defined cell populations enriched for hematopoietic stem and progenitor cells exhibit increased cycling (PMID:12763929)
• FANCC undergoes proteolytic modification by a caspase into a predominant 47-kDa ubiquitinated protein fragment. Lack of proteolytic modification at the putative cleavage site delays apoptosis. (PMID:14625294)
• Fanconi anemia C gene product regulates expression of genes involved in differentiation and inflammation. (PMID:15077170)
• FA proteins function at the level of chromatin during S phase to regulate and maintain genomic stability. (PMID:15256425)
• Inappropriate activation of Protein kinase regulated by RNA may cause mutations in FANCC> (PMID:15299030)
• Data show that the Fanconi anemia protein FANCC cooperate with key mutagenesis and repair processes that enable replication of damaged DNA. (PMID:15327776)
• spontaneous SCE levels were elevated approximately 2-fold in cells deficient in Fanconi anemia gene FANCC (PMID:15616572)
• FANCC, FANCE, and FANCD2 form a ternary complex in the Fanconi anemia DNA damage response pathway (PMID:16127171)
• analysis of two new mutations that inactivate the function of the FANCC protein (PMID:16429406)
• nuclear accumulation of FANCE does not rely solely on its nuclear localization signal motifs, but also on FANCC (PMID:16513431)
• FANCC-deficient cells are hypersensitive to DNA cross-linking reagents. (PMID:17490643)
• We found six differentially expressed proteins; among them, the checkpoint mediator protein MDC1 whose expression was disrupted in FANCC-/- cells. (PMID:17977515)
• the first report to describe hypermethylation of FANCL in leukemia (PMID:18607065)
• Differential association of alterations in FANCC and PTCH1 with that of PHF2, XPA and two breast cancer susceptibility genes (BRCA1/BRCA2) in the two age groups suggests differences in their molecular pathogenesis. (PMID:18990233)
• we identified a hepatocellular carcinoma cell line harboring an inactivating mutation of the FANCC gene, specifically causing proximal FA pathway inactivation and the classic cellular DNA interstrand-crosslinking agents-hypersensitivity phenotype (PMID:20509860)
• study found genetic interaction between Fanconi anemia(FA)gene FANCC and Ku70; results indicate FA pathway promotes homologous recombination repair of DNA double-strand breaks (DSBs) by counteracting Ku70; suggest this achieved by modification of DSBs (PMID:20538911)
• Cytoplasmic FANCA-FANCC complex was essential for NPMc stability. (PMID:20864535)
• Correct mRNA processing at a mutant TT splice donor in FANCC ameliorates the clinical phenotype in Fanconi anemia patients and is enhanced by delivery of suppressor U1 snRNAs. (PMID:20869034)
• genetic diversity in FANCA, FANCC and FANCL does not support an association of these genes with cervical cancer susceptibility in the Swedish population. (PMID:21543111)
• FANCC polymorphisms might be associated with the obstructive symptoms in allergic diseases. (PMID:21670957)
• FA DNA repair genes, FANCD2, FANCL, and FANCC, are transcriptionally upregulated differently in melanoma compared with non-melanoma skin cancer (PMID:21697891)
• deregulations of the FANCC-mediated DNA damage repair pathway and the PTCH1-associated sonic hedgehog pathway are associated with the development of early dysplastic head and neck lesions. (PMID:21861228)
• we identified faults in two genes, Fanconi C and Bloom helicase( FANCC and BLM), in six families. Faults in these genes appear to increase the risk of developing breast cancer (PMID:23028338)
• Data indicate that TLR-induced IL-1beta overproduction in FANCA- and FANCC-deficient mononuclear phagocyte cell lines and primary cells requires activation of the inflammasome. (PMID:24046015)
• FANCC interferes with UNC5A’s functions in apoptosis and suggest that FANCC may participate in developmental processes through association with the dependence receptor UNC5A. (PMID:24676280)
• The successful in vitro repair of the mutated Fanconi anemia FANCC gene using the CRISPR/Cas9 system has been described. (PMID:25545896)
• FANCC interacts and co-localizes with STMN1 at centrosomes during mitosis. We also showed that FANCC is required for STMN1 phosphorylation. (PMID:26466335)
• Israeli ATM, BLM, and FANCC heterozygous mutation carriers are not at an increased risk for developing cancer. (PMID:26778106)
• Lung adenocarcinomas in both male and female patients were associated with (a) genotypic polymorphisms of FANCC and FANCD1. (PMID:26842001)
• mutation IVS4+4A>T is the most prevalent mutation in our group of patients. This analysis of Pakistani patients also suggests that there is no significant difference between IVS4+4A>T homozygotes and the rest of the patients with regard to severity of clinical phenotype. (PMID:28425259)
• The splice-site mutation in the FANCC gene (IVS4+4A>T) accounts for most cases of Fanconi anaemia in Ashkenazi Jewish cohorts worldwide.A founder mutation described in individuals of Ashkenazi Jewish ancestry is also found in South African individuals of this origin. (PMID:29843852)
• The finding that FANCC overexpression reduced betacell apoptosis advances the potential for an alternative approach to the treatment of Diabetes mellitus caused by FANCC defects (PMID:29901137)
• This study showed that featured-metabolic alterations are readouts of functional mechanisms underlying reduced tumorigenicity driven by FANCC, demonstrating close links among cancer, aging, inflammation and DM. (PMID:29930218)
• Two truncating variants in FANCC and breast cancer risk. (PMID:31467304)
• Zika virus depletes neural stem cells and evades selective autophagy by suppressing the Fanconi anemia protein FANCC. (PMID:33073500)
• Microdeletion of 9q22.3: A patient with minimal deletion size associated with a severe phenotype. (PMID:33960642)
• In silico study of missense variants of FANCA, FANCC and FANCG genes reveals high risk deleterious alleles predisposing to Fanconi anemia pathogenesis. (PMID:34864095)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fancc	ENSDARG00000055232
mus_musculus	Fancc	ENSMUSG00000021461
rattus_norvegicus	Fancc	ENSRNOG00000016889

Protein

Protein identifiers

Fanconi anemia group C protein — Q00597 (reviewed: Q00597)

All UniProt accessions (11): Q00597, A0A024R9N2, A0A087WW44, A0A0S2Z3N5, A0A3B3IS26, A0A3B3IS92, A0A3B3ITN9, A0A3B3IU87, A0A8Q3WM43, B1ALR7, B4E3W2

UniProt curated annotations — full annotation on UniProt →

Function. DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function. May be implicated in interstrand DNA cross-link repair and in the maintenance of normal chromosome stability. Upon IFNG induction, may facilitate STAT1 activation by recruiting STAT1 to IFNGR1.

Subunit / interactions. Belongs to the multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM. This complex may also include HSP70. The complex is not found in FA patients. Interacts with ZBTB32. Upon IFNG induction, interacts with STAT1. Interacts with CDK1. Interacts with EIF2AK2; interaction between FA variants and EIF2AK2 may lead to augmented EIF2AK2 activation and cell death.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Ubiquitous.

Disease relevance. Fanconi anemia complementation group C (FANCC) [MIM:227645] 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.

RefSeq proteins (3): NP_000127, NP_001230672, NP_001230673 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000686	FANCC	Family

Pfam: PF02106

UniProt features (19 total): sequence variant 10, mutagenesis site 6, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7KZP	ELECTRON MICROSCOPY	3.1
7KZS	ELECTRON MICROSCOPY	4.2
7KZT	ELECTRON MICROSCOPY	4.2
7KZV	ELECTRON MICROSCOPY	4.2
7KZQ	ELECTRON MICROSCOPY	4.3
7KZR	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q00597-F1	82.39	0.31

Functional residue map

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

Mutagenesis-validated functional residues (6):

Position	Phenotype
64	no loss of protection from cross-linking agent-induced toxicity. no effect on ifng-induced stat1-binding.
66	no effect on protective function from mitomycin c-genotoxicity.
249	no effect on protective function from mitomycin c-genotoxicity. loss of ifng-induced stat1-binding.
251	no effect on protective function from mitomycin c-genotoxicity. loss of ifng-induced stat1-binding.
529	no effect on protective function from mitomycin c-genotoxicity.
531	no effect on protective function from mitomycin c-genotoxicity. no effect on ifng-induced stat1-binding.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6783310	Fanconi Anemia Pathway
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-9833482	PKR-mediated signaling

MSigDB gene sets: 444 (showing top): PID_FANCONI_PATHWAY, GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, E2F_Q4_01, E2F4DP1_01, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, KAUFFMANN_DNA_REPAIR_GENES, NFKB_Q6, GCM_PRKCG, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_NUCLEOTIDE_EXCISION_REPAIR, GCM_RING1, E2F1DP1_01, E2F1DP2_01, FOSTER_TOLERANT_MACROPHAGE_UP

GO Biological Process (6): DNA repair (GO:0006281), nucleotide-excision repair (GO:0006289), cellular response to oxidative stress (GO:0034599), interstrand cross-link repair (GO:0036297), protein-containing complex assembly (GO:0065003), DNA damage response (GO:0006974)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), Fanconi anaemia nuclear complex (GO:0043240)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
DNA Repair	1
Transcriptional Regulation by TP53	1
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
DNA repair	2
DNA metabolic process	1
DNA damage response	1
response to oxidative stress	1
cellular response to chemical stress	1
cellular component assembly	1
protein-containing complex organization	1
cellular response to stress	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

1173 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FANCC	FANCE	Q9HB96	999
FANCC	FANCM	Q8IYD8	999
FANCC	FANCG	O15287	999
FANCC	FANCA	O15360	999
FANCC	FANCF	Q9NPI8	999
FANCC	FANCL	Q9NW38	999
FANCC	FANCB	Q8NB91	998
FANCC	FAAP100	Q0VG06	995
FANCC	F6S8H2	F6S8H2	987
FANCC	FAAP24	Q9BTP7	982
FANCC	FANCD2	Q9BXW9	980
FANCC	FANCI	Q9NVI1	955
FANCC	BRCA2	P51587	918
FANCC	POR	P16435	911
FANCC	BRIP1	Q9BX63	906

IntAct

77 interactions, top by confidence:

A	B	Type	Score
FANCC	FANCE	psi-mi:“MI:0915”(physical association)	0.780
FANCE	FANCC	psi-mi:“MI:0915”(physical association)	0.780
FANCC	FANCA	psi-mi:“MI:0914”(association)	0.680
FANCA	FANCC	psi-mi:“MI:0915”(physical association)	0.680
FANCC	FANCA	psi-mi:“MI:0915”(physical association)	0.680
FANCC	AKT1	psi-mi:“MI:0915”(physical association)	0.610
AKT1	FANCC	psi-mi:“MI:0915”(physical association)	0.610
FANCC	AKT1	psi-mi:“MI:2364”(proximity)	0.610
FAAP20	FANCA	psi-mi:“MI:0914”(association)	0.590
SPTAN1	FANCC	psi-mi:“MI:0915”(physical association)	0.590
FANCC	SPTAN1	psi-mi:“MI:0915”(physical association)	0.590
FANCC	HSP90B1	psi-mi:“MI:0915”(physical association)	0.580
FANCC	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
FBXW7	FANCC	psi-mi:“MI:2364”(proximity)	0.520
SMAD4	FANCC	psi-mi:“MI:2364”(proximity)	0.520
EGFR	FANCC	psi-mi:“MI:2364”(proximity)	0.520

BioGRID (220): FANCC (Affinity Capture-MS), FANCC (Affinity Capture-Western), FANCC (Affinity Capture-Western), FANCC (Affinity Capture-MS), FANCC (Affinity Capture-MS), FANCC (Affinity Capture-MS), FANCC (Affinity Capture-MS), FANCC (Affinity Capture-Western), FANCC (Affinity Capture-Western), FANCC (Affinity Capture-Western), FANCC (Two-hybrid), FANCC (Two-hybrid), FANCC (Reconstituted Complex), CTBP1 (Two-hybrid), FANCC (Affinity Capture-Western)

ESM2 similar proteins: A0JM49, A2AKG8, B0V0U5, B1AUR6, B3DIY3, C5J7W8, E1BGH8, E1C2Z0, E7FGT5, E7FH61, E9PVA8, E9Q368, F6S215, O08662, O19104, O35870, O43149, O60287, P35608, P78527, Q00597, Q13315, Q14146, Q3TQQ9, Q3URQ0, Q4V847, Q571H0, Q5JWR5, Q5TYP4, Q5VW36, Q5WNI9, Q5XI94, Q5ZKU4, Q5ZM41, Q62388, Q6A009, Q6PQD5, Q6TNU3, Q6ZRQ5, Q75QN2

Diamond homologs: O19104, O35870, P50652, Q00597

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FANCC	up-regulates	STAT1
FANCC	“form complex”	“Fanconi anemia core complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 46 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
Downstream signal transduction	5	47.6×	2e-05
FLT3 Signaling	5	43.3×	2e-05
Fanconi Anemia Pathway	5	34.8×	3e-05
Transcriptional regulation by RUNX2	5	31.7×	3e-05
Signaling by SCF-KIT	5	31.0×	3e-05
PKR-mediated signaling	7	24.7×	7e-06
Extra-nuclear estrogen signaling	5	21.3×	1e-04
Deubiquitination	5	15.5×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
interstrand cross-link repair	5	49.1×	2e-05
cellular response to epidermal growth factor stimulus	5	36.1×	5e-05
epidermal growth factor receptor signaling pathway	6	33.8×	2e-05
positive regulation of miRNA transcription	5	33.0×	6e-05
negative regulation of cell growth	6	19.6×	8e-05
transforming growth factor beta receptor signaling pathway	5	18.1×	1e-03
negative regulation of neuron apoptotic process	5	12.6×	2e-03
DNA damage response	9	10.9×	2e-05

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1251 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	82
Likely pathogenic	67
Uncertain significance	563
Likely benign	354
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1049581	NM_000136.3(FANCC):c.166-165_250+3del	Pathogenic
1050046	NM_000136.3(FANCC):c.1272G>A (p.Trp424Ter)	Pathogenic
1070636	NM_000136.3(FANCC):c.355_358del (p.Ser119fs)	Pathogenic
1071693	NC_000009.11:g.(?97873735)(97897794_?)del	Pathogenic
1072466	NM_000136.3(FANCC):c.228del (p.Cys75_Trp76insTer)	Pathogenic
1073407	NM_000136.3(FANCC):c.201del (p.Ile67fs)	Pathogenic
1073431	NC_000009.11:g.(?97876901)(97879682_?)del	Pathogenic
1074074	NM_000136.3(FANCC):c.226del (p.Trp76fs)	Pathogenic
1075326	NM_000136.3(FANCC):c.319_340dup (p.Ile114delinsThrIleLysThrTer)	Pathogenic
12044	NM_000136.3(FANCC):c.553C>T (p.Arg185Ter)	Pathogenic
12045	NM_000136.3(FANCC):c.456+4A>T	Pathogenic
12046	NM_000136.3(FANCC):c.37C>T (p.Gln13Ter)	Pathogenic
12049	NM_000136.3(FANCC):c.67del (p.Asp23fs)	Pathogenic
12052	FANCC, 250-BP DEL	Pathogenic
1406812	NM_000136.3(FANCC):c.863del (p.Pro288fs)	Pathogenic
1454577	NC_000009.11:g.(?98009704)(98009808_?)del	Pathogenic
1457889	NC_000009.11:g.(?97863979)(97934439_?)del	Pathogenic
1458684	NC_000009.11:g.(?98002921)(98011661_?)del	Pathogenic
1459304	NC_000009.11:g.(?97861619)(97869538_?)del	Pathogenic
1685809	NM_000136.3(FANCC):c.259C>T (p.Gln87Ter)	Pathogenic
1731168	NM_000136.3(FANCC):c.341_342del (p.Ile114fs)	Pathogenic
1745846	NM_000136.3(FANCC):c.517dup (p.Arg173fs)	Pathogenic
1808833	GRCh37/hg19 9q22.31-22.32(chr9:95711603-98469214)x1	Pathogenic
188926	NM_000136.3(FANCC):c.65G>A (p.Trp22Ter)	Pathogenic
2021674	NM_000136.3(FANCC):c.49_56del (p.Gln17fs)	Pathogenic
219667	NM_000136.2(FANCC):c.997-?_1154+?del	Pathogenic
237062	NM_000136.2(FANCC):c.-78-?_250+?del	Pathogenic
2422436	NC_000009.11:g.(?97897618)(97912379_?)del	Pathogenic
2565545	NM_000136.3(FANCC):c.212T>A (p.Leu71Ter)	Pathogenic
2585976	NM_000136.3(FANCC):c.760del (p.Met254fs)	Pathogenic

SpliceAI

5023 predictions. Top by Δscore:

Variant	Effect	Δscore
9:95111459:CCA:C	donor_loss	1.0000
9:95111460:CACC:C	donor_loss	1.0000
9:95111461:A:AT	donor_loss	1.0000
9:95111462:C:T	donor_loss	1.0000
9:95117401:A:C	acceptor_gain	1.0000
9:95135507:C:CT	acceptor_gain	1.0000
9:95135508:A:T	acceptor_gain	1.0000
9:95149921:A:AC	donor_gain	1.0000
9:95149922:C:CA	donor_gain	1.0000
9:95149922:CA:C	donor_gain	1.0000
9:95149922:CAG:C	donor_gain	1.0000
9:95150084:CATT:C	acceptor_gain	1.0000
9:95150088:C:CC	acceptor_gain	1.0000
9:95171077:ACCG:A	donor_gain	1.0000
9:95171078:CCGC:C	donor_gain	1.0000
9:95171140:CCAT:C	acceptor_gain	1.0000
9:95171141:CATC:C	acceptor_gain	1.0000
9:95171838:T:TA	donor_gain	1.0000
9:95172035:A:AC	donor_gain	1.0000
9:95172036:C:CC	donor_gain	1.0000
9:95172144:CACC:C	acceptor_gain	1.0000
9:95172146:CC:C	acceptor_gain	1.0000
9:95172147:CC:C	acceptor_gain	1.0000
9:95203903:CATAG:C	donor_gain	1.0000
9:95203907:G:C	donor_gain	1.0000
9:95247512:GAATC:G	acceptor_gain	1.0000
9:95247514:ATCC:A	acceptor_loss	1.0000
9:95247515:TC:T	acceptor_gain	1.0000
9:95247516:CC:C	acceptor_gain	1.0000
9:95247516:CCT:C	acceptor_loss	1.0000

AlphaMissense

3637 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:95135462:A:G	W243R	0.984
9:95135462:A:T	W243R	0.984
9:95126552:G:C	F291L	0.968
9:95126552:G:T	F291L	0.968
9:95126554:A:G	F291L	0.968
9:95125128:A:C	F318L	0.967
9:95125128:A:T	F318L	0.967
9:95125130:A:G	F318L	0.967
9:95135442:G:C	S249R	0.966
9:95135442:G:T	S249R	0.966
9:95135444:T:G	S249R	0.966
9:95249160:G:C	F44L	0.956
9:95249160:G:T	F44L	0.956
9:95249162:A:G	F44L	0.956
9:95126556:A:T	I290K	0.955
9:95111508:G:C	F428L	0.954
9:95111508:G:T	F428L	0.954
9:95111510:A:G	F428L	0.954
9:95135460:C:A	W243C	0.946
9:95135460:C:G	W243C	0.946
9:95135437:T:A	E251V	0.939
9:95135436:T:A	E251D	0.935
9:95135436:T:G	E251D	0.935
9:95240736:G:C	S86R	0.932
9:95240736:G:T	S86R	0.932
9:95240738:T:G	S86R	0.932
9:95149998:A:T	L204H	0.930
9:95249249:A:G	W15R	0.928
9:95249249:A:T	W15R	0.928
9:95149998:A:G	L204P	0.925

dbSNP variants (sampled 300 via entrez): RS1000010626 (9:95156832 T>C), RS1000025682 (9:95129239 A>G), RS1000036037 (9:95170707 C>A,T), RS1000037776 (9:95114474 G>A), RS1000061994 (9:95099869 A>G), RS1000083796 (9:95177345 T>C), RS1000093172 (9:95201450 C>T), RS1000098667 (9:95108765 C>T), RS1000125479 (9:95202990 A>G), RS1000128480 (9:95290206 G>C), RS1000140449 (9:95113251 C>T), RS1000202219 (9:95316858 G>A,T), RS1000208044 (9:95181443 C>T), RS1000211895 (9:95227732 C>T), RS1000236781 (9:95267934 A>T)

Disease associations

OMIM: gene MIM:613899 | disease phenotypes: MIM:227650, MIM:227645, MIM:167000, MIM:109400

GenCC curated gene-disease

Disease	Classification	Inheritance
Fanconi anemia complementation group C	Definitive	Autosomal recessive
Fanconi anemia	Supportive	Autosomal recessive
colorectal cancer	Limited	Autosomal dominant
ovarian cancer	Limited	Autosomal dominant
prostate cancer	Limited	Autosomal dominant
malignant pancreatic neoplasm	Limited	Autosomal dominant
breast cancer	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Fanconi anemia complementation group C	Definitive	AR

Mondo (14): Fanconi anemia (MONDO:0019391), hereditary neoplastic syndrome (MONDO:0015356), Fanconi anemia complementation group C (MONDO:0009213), breast cancer (MONDO:0007254), Fanconi anemia complementation group A (MONDO:0009215), ovarian cancer (MONDO:0008170), colon carcinoma (MONDO:0002032), familial ovarian cancer (MONDO:0016248), nevoid basal cell carcinoma syndrome (MONDO:0007187), hereditary breast ovarian cancer syndrome (MONDO:0003582), primary ovarian failure (MONDO:0005387), colorectal cancer (MONDO:0005575), prostate cancer (MONDO:0008315), malignant pancreatic neoplasm (MONDO:0009831)

Orphanet (7): Fanconi anemia (Orphanet:84), Inherited cancer-predisposing syndrome (Orphanet:140162), Rare ovarian cancer (Orphanet:213500), Gorlin syndrome (Orphanet:377), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), OBSOLETE: Familial ovarian cancer (Orphanet:213517), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

137 total (30 of 137 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:0000081	Duplicated collecting system
HP:0000083	Renal insufficiency
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000104	Renal agenesis
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:0000325	Triangular face
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000364	Hearing abnormality
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000453	Choanal atresia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005273_4	Polycystic ovary syndrome	5.000000e-13
GCST008362_186	Birth weight	1.000000e-25
GCST008363_68	Offspring birth weight	4.000000e-09
GCST90002383_517	Hematocrit	8.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004348	hematocrit

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D001478	Basal Cell Nevus Syndrome	C04.182.089.530.690.150; C04.557.470.200.165.150; C04.557.470.565.165.150; C04.700.175; C05.116.099.105; C05.500.470.690.150; C07.320.450.670.130; C16.131.077.130; C16.320.700.175
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
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
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
FANCC Loss-of-function	Cisplatin + Melphalan + Chlorambucil + Mitomycin + Gemcitabine	Pancreatic Cancer	Sensitivity/Response	CIViC D	EID1307

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4647554	AOPEP, FANCC		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects expression, decreases expression, decreases response to substance, increases response to substance	5
Benzo(a)pyrene	affects methylation, decreases expression	4
sodium arsenite	decreases expression, increases abundance	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Testosterone	affects cotreatment, decreases expression, increases expression	2
Valproic Acid	decreases expression, affects expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
riddelliine	increases metabolic processing, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	affects methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	decreases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4(2’-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline	decreases expression	1
Temozolomide	affects response to substance	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Lycopene	decreases expression	1
Asbestos	affects response to substance	1
Calcitriol	decreases expression, affects cotreatment	1
Cannabidiol	decreases expression	1
Carbamazepine	affects expression	1
Carmustine	affects response to substance	1
Chlorambucil	increases response to substance	1

Cellosaurus cell lines

17 cell lines: 10 transformed cell line, 4 cancer cell line, 2 finite cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_1635	Panc 03.27	Cancer cell line	Female
CVCL_1857	BD-215	Transformed cell line	Male
CVCL_AK34	GM12794	Transformed cell line	Female
CVCL_AK36	HSC 536N	Transformed cell line	Male
CVCL_AK44	GM16755	Finite cell line	Female
CVCL_AK45	GM20731	Transformed cell line	Female
CVCL_AK46	GM20732	Transformed cell line	Male
CVCL_E3YF	HSC 536 FANCC	Transformed cell line	Male
CVCL_F125	GM00449	Finite cell line	Female
CVCL_F126	GM13136	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	PHASE4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia
NCT02567331	PHASE4	COMPLETED	A Study of Capecitabine (Xeloda) in Patients With Metastatic Colorectal Cancer