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

dbSNP: rs370974124

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000218828	SCV000279991	uncertain significance	not provided	2023-08-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 4 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Identified in an individual with Wilms tumor who also harbored a pathogenic CHEK2 variant (Parsons et al., 2016); This variant is associated with the following publications: (PMID: 8882868, Gordon2000[Book], 26822237, 29922827)
Mendelics	RCV000505654	SCV000838338	likely pathogenic	Fanconi anemia complementation group C	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV000818572	SCV000959192	uncertain significance	Fanconi anemia	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg555*) in the FANCC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the FANCC protein. This variant is present in population databases (rs370974124, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Wilms tumor (PMID: 26822237). ClinVar contains an entry for this variant (Variation ID: 234905). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant 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.
Ambry Genetics	RCV002399801	SCV002708399	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-05	criteria provided, single submitter	clinical testing	The p.R555* variant (also known as c.1663C>T), located in coding exon 14 of the FANCC gene, results from a C to T substitution at nucleotide position 1663. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration occurs at the 3' terminus of theFANCC gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last four amino acids of the protein. The exact functional effect of this alteration is unknown. This variant was reported in a child with Wilms tumor, who had whole exome sequencing, as part of a study of unselected children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumors; her tumor did not show loss of heterozygosity and the variant was not de novo (Parsons DW et al. JAMA Oncol. 2016 May;2:616-624). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000505654	SCV003833907	uncertain significance	Fanconi anemia complementation group C	2021-07-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000505654	SCV004196675	uncertain significance	Fanconi anemia complementation group C	2023-05-26	criteria provided, single submitter	clinical testing
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.
Counsyl	RCV000505654	SCV001132191	uncertain significance	Fanconi anemia complementation group C	2019-07-07	no assertion criteria provided	clinical testing