Submissions for variant NM_000136.3(FANCC):c.487_490del (p.Glu163fs)

dbSNP: rs730881708

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160466	SCV000211031	likely pathogenic	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29922827, 30322717, 32546565, 34308366, 26681312)
Invitae	RCV000528984	SCV000626250	pathogenic	Fanconi anemia	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu163Ilefs*30) in the FANCC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant is present in population databases (rs730881708, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182465). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410607	SCV000695433	likely pathogenic	Fanconi anemia complementation group C	2022-09-06	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.487_490delGAGA (p.Glu163IlefsX30) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 251214 control chromosomes. c.487_490delGAGA has been reported in the literature in an individual affected with ovarian cancer (example, Susswein_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000410607	SCV001163626	pathogenic	Fanconi anemia complementation group C	2024-03-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001023180	SCV001185015	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-03	criteria provided, single submitter	clinical testing	The c.487_490delGAGA variant, located in coding exon 5 of the FANCC gene, results from a deletion of 4 nucleotides at nucleotide positions 487 to 490, causing a translational frameshift with a predicted alternate stop codon (p.E163Ifs*30). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel; this patient had ovarian cancer and RAD51C c.404+2C>T variant (Susswein LR et al. Genet. Med. 2016 08;18:823-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000410607	SCV001478122	pathogenic	Fanconi anemia complementation group C	2020-12-15	criteria provided, single submitter	research
Genetic Services Laboratory, University of Chicago	RCV000160466	SCV002067533	likely pathogenic	not provided	2020-09-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCC gene demonstrated a 4 base pair deletion in exon 6, c.487_490del. This deletion results in an amino acid frameshift with a premature stop codon 29 amino acids downstream of the change, p.Glu163Ilefs*30. The p.Glu163Ilefs*30 change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated FANCC protein with potentially abnormal function. This sequence change has been described in the gnomAD database in six individuals with an overall population frequency of 0.002% (dbSNP rs950623649). The p.Glu163Ilefs*30 change has previously been observed in the heterozygous state in one individual with ovarian cancer (PMID: 26681312). Loss of function variants are known to be pathogenic in the FANCC gene. These collective evidences suggest this sequence change is a likely pathogenic sequence change.
Sema4, Sema4	RCV000528984	SCV002535105	likely pathogenic	Fanconi anemia	2021-08-11	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000410607	SCV002796732	pathogenic	Fanconi anemia complementation group C	2021-10-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000410607	SCV000486096	likely pathogenic	Fanconi anemia complementation group C	2017-12-28	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000410607	SCV001365297	pathogenic	Fanconi anemia complementation group C	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.