FANCC rs121908078: What Your Genotype Means
The rs121908078 variant, also known as c.456+4A>T, is a genetic change in the FANCC gene. It is recognized as a founder mutation primarily associated with carrier status for autosomal recessive Fanconi anemia, particularly within the Ashkenazi Jewish population.
What each genotype means
Typical genetic profile
This genotype represents the common, non-pathogenic sequence at this location in the FANCC gene. Individuals with this profile do not carry the specific splice-donor mutation associated with Fanconi anemia group C carrier status.
This is the most common genotype found in the general population.
Fanconi anemia carrier status
This genotype indicates you carry one copy of the c.456+4A>T mutation (also historically referred to as IVS4+4A>T). As Fanconi anemia is an autosomal recessive condition, carriers are typically unaffected, but they have a 50% chance of passing this variant to their children. If your partner is also a carrier, there is a risk of having a child affected by Fanconi anemia group C.
This variant is found primarily in individuals of Ashkenazi Jewish ancestry, with a carrier frequency estimated between 1 in 83 and 1 in 100.
Potential Fanconi anemia risk
This genotype indicates you carry two copies of the c.456+4A>T mutation. Inheriting two pathogenic variants in the FANCC gene is associated with Fanconi anemia group C, a condition that can lead to bone marrow failure and increased cancer risk. Please consult with a clinical geneticist or your healthcare provider to discuss these results and their clinical implications.
This genotype is extremely rare in the general population.
Understanding the Variant
The variant rs121908078 is a specific change in the DNA sequence of the FANCC gene, located on chromosome 9. In scientific literature, it is frequently referred to by its legacy nomenclature, IVS4+4A>T, or as c.456+4A>T. This variant is classified as a splice-donor mutation. Splice sites are critical sequences in DNA that act as signals for the cell to correctly assemble the final messenger RNA (mRNA) molecule, which serves as a blueprint for protein production. When a mutation occurs at a splice-donor site, it can disrupt the normal splicing process, often leading to the skipping of an exon or the inclusion of incorrect genetic information. This disruption typically results in the production of a non-functional or unstable protein, which is the underlying mechanism by which this variant contributes to its associated clinical conditions.
The Role of the FANCC Gene
The FANCC gene provides instructions for making a protein that is part of the Fanconi anemia (FA) core complex. This complex is essential for the Fanconi anemia pathway, a critical cellular mechanism responsible for repairing damaged DNA, specifically interstrand crosslinks. When DNA is damaged, the FA pathway coordinates the repair process to maintain genomic stability. If the FANCC protein is absent or non-functional, the entire FA pathway is disrupted. Consequently, cells become unable to efficiently repair DNA damage, leading to the accumulation of genetic errors over time. This instability is the hallmark of Fanconi anemia, a rare, inherited disorder characterized by bone marrow failure, an increased risk of developing certain cancers, and various physical abnormalities. The severity of the condition often depends on whether an individual has inherited functional copies of the gene from both parents.
Research and Clinical Significance
Research has established rs121908078 as a pathogenic founder mutation, meaning it is found at a higher frequency in specific populations due to historical demographic factors. It is well-documented in medical literature as a cause of Fanconi anemia when inherited in a compound heterozygous or homozygous state. Because Fanconi anemia is an autosomal recessive condition, individuals who carry only one copy of this variant are typically considered carriers. Carriers generally do not exhibit the symptoms of the disease themselves but have a 25% chance of passing the variant to their children if their partner is also a carrier. The evidence linking this specific variant to Fanconi anemia is strong, and it is widely recognized in clinical genetics as a significant marker for carrier screening, particularly for individuals of Ashkenazi Jewish descent.
What This Information Means for You
If you have received information regarding your status for the rs121908078 variant, it is important to understand that this is a carrier status marker. Being a carrier does not mean you have Fanconi anemia, but it does provide information about your genetic makeup that may be relevant for family planning. Genetic testing results should always be interpreted in the context of your personal and family medical history. If you are concerned about your carrier status or the potential risks to future children, the most appropriate step is to consult with a certified genetic counselor or a medical professional. They can provide personalized guidance, explain the implications of your results, and discuss options for further testing or reproductive planning. Never use genetic data to make independent medical decisions or to diagnose a condition; always rely on the expertise of qualified healthcare providers.
How common is this variant?
The rs121908078 variant is a known founder mutation in the Ashkenazi Jewish population, with an allele frequency typically reported between 0.005 and 0.01 in this group.
Frequently asked questions
What is a carrier of Fanconi anemia?
A carrier of Fanconi anemia has one altered copy of a gene associated with the condition but does not typically show symptoms. Carriers can pass the altered gene to their children, who may be at risk if they inherit an altered copy from both parents.
Is rs121908078 the same as IVS4+4A>T?
Yes, rs121908078 and IVS4+4A>T refer to the same genetic variant. IVS4+4A>T is an older, legacy name for the mutation, while rs121908078 is the modern identifier used in databases like dbSNP.
Should I be tested for this variant?
Carrier screening is often recommended for individuals of Ashkenazi Jewish descent due to the higher frequency of certain genetic conditions. You should discuss the benefits and limitations of genetic testing with a healthcare provider or genetic counselor.
Does having this variant mean I will get cancer?
Being a carrier of a Fanconi anemia variant does not mean you will develop cancer. However, because the FA pathway is involved in DNA repair, it is important to discuss your specific genetic results and family history with a doctor to understand your personal health context.
Sources & further reading
Educational information only, last refreshed 10/15/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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