Submissions for variant NM_000136.3(FANCC):c.1628C>A (p.Ser543Ter)

gnomAD frequency: 0.00001  dbSNP: rs867319477

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409524	SCV000485726	likely pathogenic	Fanconi anemia complementation group C	2016-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000657699	SCV000779448	likely pathogenic	not provided	2016-10-10	criteria provided, single submitter	clinical testing	This variant is denoted FANCC c.1628C>A at the cDNA level and p.Ser543Ter (S543X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TAA), and is predicted to cause loss of normal protein function through protein truncation. Even though this truncation occurs near the end of the gene and nonsense-mediated decay is not expected to occur, it is significant since the last 49 amino acids are no longer translated. Furthermore, the truncation would disrupt the region of interaction with cdc2 (Gordon 2000). Although this variant has not, to our knowledge, been reported in the literature, we consider it to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059596	SCV001224223	pathogenic	Fanconi anemia	2019-10-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the FANCC protein. Other variant(s) that disrupt this region (p.Arg548*) have been determined to be pathogenic (PMID: 8103176, 8882868, 24584348). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has not been reported in the literature in individuals with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 370412). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FANCC gene (p.Ser543*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acids of the FANCC protein.
Revvity Omics, Revvity	RCV000409524	SCV002024580	likely pathogenic	Fanconi anemia complementation group C	2019-03-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409524	SCV005057616	likely pathogenic	Fanconi anemia complementation group C	2023-12-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003897826	SCV004714606	likely pathogenic	FANCC-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The FANCC c.1628C>A variant is predicted to result in premature protein termination (p.Ser543*). This variant has been reported in an individual with Ewing sarcoma (Gillani et al. 2022. PubMed ID: 35512711. Table S4). Although this variant occurs at the last exon of the gene, a different nonsense variant (p.Arg548*) located downstream has been reported to be pathogenic (De Rocco et al. 2014. PubMed ID: 24584348; Murer-Orlando et al. 1993. PubMed ID: 8103176). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in FANCC are expected to be pathogenic. This variant is interpreted as likely pathogenic.