ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1663C>T (p.Arg555Ter) (rs370974124)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000505654 SCV000599937 pathogenic Fanconi anemia, complementation group C 2014-01-30 no assertion criteria provided research This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It would be pathogenic in a recessive state; heterozygotes would be carriers for the condition. It was found once in our study paternally inherited in a 5-year-old female with Wilms tumor; LOH was not detected in this region in the tumor. The patient also had a heterozygous frameshift variant in DIS3L2, with the tumor showing LOH for that region, and a heterozygous frameshift CHEK2 variant.
GeneDx RCV000218828 SCV000279991 likely pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1663C>T at the cDNA level and p.Arg555Ter (R555X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). This variant has been observed in one child undergoing whole exome sequencing with a history of a Wilm's tumor (Parsons 2016). FANCC Arg555Ter is located in the last exon of the FANCC gene and results in the loss of the last 4 amino acids. Even though nonsense-mediated decay is not expected to occur based on its location within the gene, this variant is predicted to cause loss of normal protein function by disruption of the cdc2 binding site via protein truncation. In addition, Lo Ten Foe et al. (1996) showed that an adjacent nonsense variant (Leu554Ter), lacking the last 5 amino acids in FANCC, failed to correct crosslinker hypersensitivity, suggesting a functional requirement for these c-terminal amino acids. Based on currently available evidence, we consider FANCC Arg555Ter to be a likely pathogenic variant.
Invitae RCV000818572 SCV000959192 uncertain significance Fanconi anemia 2018-08-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the FANCC gene (p.Arg555*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 4 amino acids of the FANCC protein. This variant is present in population databases (rs370974124, ExAC 0.02%). This variant has been observed in an individual affected with Wilms tumor (PMID: 26822237). ClinVar contains an entry for this variant (Variation ID: 234905). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000505654 SCV000838338 likely pathogenic Fanconi anemia, complementation group C 2018-07-02 criteria provided, single submitter clinical testing

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