FANCC

protein-coding

FA complementation group C, the group of FA core complex|FA complementation groups

Gene summary

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. [provided by RefSeq, Jul 2008]

Previous symbols:

FACC

MANE transcript

NM_000136.3

Inheritance

AR, AD

ClinVar variants

P:336U:966B:541

Top phenotype

Fanconi anemia, complementation group C

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr9:95,099,054-95,426,796

External References & Databases

Ensembl (ENSG00000158169)

Transcript & Mutation Effects

hg38 • Region Span ~327.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fanconi anemia complementation group CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009213

Submitter: Labcorp Genetics (formerly Invitae)

prostate cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008315

Submitter: Ambry Genetics

Fanconi anemia complementation group CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009213

Submitter: ClinGen

There is abundant evidence published associating the FANCC gene with Fanconi anemia complementation group C, since the gene-disease relationship was first proposed by Gavish et al. (1992). Multiple case level studies have been performed with FA patients that have variants in the FANCC gene. Eight of the FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM) are part of a nuclear multiprotein core complex which triggers activating monoubiquitination of the FANCD2 in the FA/BRCA DNA repair pathway. Multiple Fancc deficient mouse models have been established to show consistent phenotypes with FA patients including impaired fertility, chromosome breakage and cross linker sensitivity, and spontaneous hematologic sequelae. All of these types of evidence are consistent with a definitive relationship between the FANCC gene and Fanconi anemia complementation group C.

colorectal cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005575

Submitter: Ambry Genetics

breast cancerNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: Ambry Genetics

Fanconi anemia complementation group CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009213

Submitter: G2P

Fanconi anemia complementation group CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009213

Submitter: Myriad Women's Health

malignant pancreatic neoplasmLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009831

Submitter: Ambry Genetics

Fanconi anemia complementation group CDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009213

Submitter: Natera

Fanconi anemia complementation group CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009213

Submitter: PanelApp Australia

Fanconi anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

familial pancreatic carcinomaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0015278

Submitter: Natera

hereditary breast carcinomaNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0016419

Submitter: Natera

ovarian cancerLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008170

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Fanconi anemia, complementation group CAR

Manifestation: Audiologic/Otolaryngologic; Allergy/Immunology/Infectious; Cardiovascular; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Renal

Intervention: Allergy/Immunology/Infectious; Cardiovascular; Hematologic; Oncologic

Rationale: Specific treatments can help manifestations (eg, oral androgens for blood counts; G-CSF for neutrophil count); HSCT can be curative, but solid tumor risk may remain; Surveillance for complications such as bone marrow failure is recommended; Fanconi anemia can involve congenital cardiac (and other) anomalies, and awareness may allow early management

Refs: 1574115; 9272737; 10431244; 20301575; 22160080; 22701786; 23028338

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FANCC variants in ClinVar

17 Conditions Cataloged

Hereditary cancer-predisposing syndromeTotal: 1417

Fanconi anemiaTotal: 1230

Fanconi anemia complementation group CTotal: 510

not providedTotal: 464

not specifiedTotal: 214

FANCC-related disorderTotal: 66

Malignant tumor of breastTotal: 37

Fanconi anemia complementation group ATotal: 31

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000136.3. 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	1 clinvar	1 clinvar	13 clinvar	437 clinvar	5 clinvar	457
missense	1 clinvar	5 clinvar	942 clinvar	96 clinvar	3 clinvar	1047
nonsense	37 clinvar	55 clinvar	3 clinvar			95
start loss	1 clinvar	3 clinvar				4
frameshift	77 clinvar	84 clinvar	4 clinvar			165
splice donor/acceptor (+/-2bp)	10 clinvar	61 clinvar	4 clinvar			75
Total	127	209	966	533	8	1843

Highest pathogenic variant AF is 0.00021189381

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000136.3	RefSeq	NP_000127.2	14	MANE Select
ENST00000289081.8	Ensembl	ENSP00000289081.3	14	MANE Select
NM_001243743.2	RefSeq	NP_001230672.1	14	Standard
NM_001243744.2	RefSeq	NP_001230673.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fanconi anemia pathway - Homo sapiens (human)
TP53 Regulates Transcription of DNA Repair Genes
Fanconi Anemia Pathway
DNA Repair
Gene expression (Transcription)

Biological Process

myeloid cell homeostasis
DNA repair
nucleotide-excision repair
germ cell development
removal of superoxide radicals

Molecular Function

protein binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol
Fanconi anaemia nuclear complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000289081
Coding exons: 14
Length: 218656
Individuals with no LoFs: 125645
Homozygous LoFs: 0
Heterozygous LoFs: 103
Defined: 125748
p: 0.000410

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.194	306	297	1.03	0.0000161	3623
Missense (PolyPhen)		105	92.053	1.1407		1244
Synonymous	-0.722	122	112	1.09	0.00000665	1100
Loss of Function	1.36	24	32.3	0.742	0.00000166	350

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00060	0.00060	rare
South Asian	0.00036	0.00036	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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. {ECO:0000269|PubMed:11520787}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:11520787, ECO:0000269|PubMed:15299030, ECO:0000269|PubMed:1574115, ECO:0000269|PubMed:8128956, ECO:0000269|PubMed:8499901, ECO:0000269|PubMed:8844212, ECO:0000269|PubMed:9242535}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.518

Intolerance Scores

LoFtool: 0.951
RVIS EVS: 0.35
RVIS percentile EVS: 74.58

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.804

Gene Damage Prediction

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