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FANCL
FA complementation group L
The FANCL gene encodes a protein essential for DNA repair, playing a critical role in the Fanconi Anaemia pathway that responds to DNA damage and maintaining genomic stability. FANCL (FA complementation group L) is a gene that provides instructions for making a protein involved in the Fanconi Anaemia (FA) pathway, a crucial system for repairing damaged DNA.
FANCL is located on the short (p) arm of chromosome 2, at band 2p16.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The FANCL gene, also known as FA complementation group L, provides instructions for creating a protein vital for DNA repair processes within cells. This protein is a key component of the Fanconi Anaemia (FA) pathway, a complex network responsible for detecting and repairing specific types of DNA damage, particularly interstrand crosslinks [PMID:16013919]. Proper functioning of the FANCL protein is essential for maintaining genomic integrity and preventing genetic mutations that can lead to disease.
Dysfunction of the FANCL protein, often caused by pathogenic genetic variants, can disrupt this critical DNA repair pathway. This can increase an individual's susceptibility to certain inherited conditions, including Fanconi Anaemia, and may contribute to an elevated risk of developing various cancers [PMID:28779951].
What the gene does
The FANCL gene encodes a ubiquitin ligase, a type of enzyme that plays a crucial role in the Fanconi Anaemia (FA) pathway. Specifically, the FANCL protein is responsible for monoubiquitinating FANCD2 and FANCI, two other proteins within the FA core complex [PMID:15610816, PMID:16013919]. This monoubiquitination step is a critical activation event, enabling the FANCD2-FANCI complex to localize to sites of DNA damage. Once at these sites, the activated complex facilitates the repair of interstrand crosslinks, which are particularly harmful forms of DNA damage where the two strands of the DNA double helix become covalently linked.
This process is fundamental for safeguarding the cell's genetic material. Without functional FANCL, the FA pathway cannot properly activate FANCD2 and FANCI, leading to an accumulation of unrepaired DNA damage. Such damage can interfere with DNA replication and transcription, potentially resulting in chromosomal instability, cell cycle arrest, and increased susceptibility to apoptosis or malignant transformation [PMID:16013919].
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Chromosome location
The FANCL gene is situated on chromosome 2 at position 2p16.1. This specifies its precise location on the short (p) arm of chromosome 2, within region 1, band 6, and sub-band 1. The gene spans 4,374 base pairs of DNA.
Protein structure
The FANCL protein consists of 375 amino acids. It features a notable UBC-RWD region (URD) spanning amino acids 104-294, which is involved in protein-protein interactions and catalytic activity. Additionally, a degenerate RING-type zinc finger domain is located between amino acids 307-363, which is characteristic of E3 ubiquitin ligases and plays a key role in substrate recognition and ubiquitination.
Key variants
Genetic variations within the FANCL gene can influence its function. These variations range from single nucleotide changes to larger deletions or insertions. Pathogenic variants typically disrupt the protein's ability to participate in DNA repair, leading to diminished function or a complete loss of the encoded protein. The clinical significance of any identified variant is often determined by its impact on protein structure and function, and correlation with established disease-causing mutations.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
g.58232113del | - | Pathogenic | ★★☆☆ | Fetal anomalies with a likely genetic cause |
c.1017_1018insA | p.Glu340fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.1023_1031del | p.Trp341_Gly344delinsTer | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.1029dup | p.Gly344fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.13del | p.Glu5fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia complementation group L |
c.378del | p.Val127fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.636G>A | p.Trp212Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.64A>T | p.Lys22Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.822G>A | p.Trp274Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
c.89C>A | p.Ser30Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fanconi anemia |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the FANCL gene are primarily associated with Fanconi Anaemia (FA), a rare inherited disorder. FA is characterised by progressive bone marrow failure, increased cancer risk, and a variety of congenital abnormalities affecting multiple organ systems. Although not explicitly listed in the associated conditions for this tier, research indicates that FANCL variants contribute to a broader category of cancer predisposition through their role in DNA repair.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic FANCL variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
In the UK, the FANCL gene is included in several NHS national genomic testing panels, indicating its recognised clinical significance. It has a 'green' RAG (Red Amber Green) rating for conditions such as Adult solid tumours cancer susceptibility, Childhood solid tumours, and Cytopenias and congenital anaemias. This signifies that there is strong evidence for the gene's association with these conditions and it is routinely analysed in NHS genomic laboratories. It is also part of panels for Foetal anomalies and Monogenic short stature, reflecting its broad involvement in developmental and disease pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the FANCL gene?
The FANCL gene encodes a protein that acts as a ubiquitin ligase within the Fanconi Anaemia (FA) pathway. Its main function is to activate other FA proteins, like FANCD2 and FANCI, through a process called monoubiquitination, which is essential for repairing damaged DNA, particularly interstrand crosslinks.
How is FANCL related to cancer?
Variants in the FANCL gene can impair the cell's ability to repair DNA damage effectively. This impaired DNA repair can lead to an accumulation of mutations and genomic instability, which are known factors that increase an individual's susceptibility to developing various types of cancer.
Is Fanconi Anaemia inherited?
Yes, Fanconi Anaemia, which can be caused by pathogenic variants in the FANCL gene, is an inherited condition. It typically follows an autosomal recessive inheritance pattern, meaning an individual must inherit two copies of the altered gene (one from each parent) to develop the condition.