Submissions for variant NM_000136.3(FANCC):c.455dup (p.Asn152fs)

dbSNP: rs774170058

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000465895	SCV000549961	pathogenic	Fanconi anemia	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn152Lysfs*9) 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 (rs774170058, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 16429406). ClinVar contains an entry for this variant (Variation ID: 409657). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000482020	SCV000566026	pathogenic	not provided	2023-03-09	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); Observed in individuals with colorectal, medulloblastoma, melanoma, and stomach cancer (Lu et al., 2015; Huang et al., 2018; Waszak et al., 2018; Stolarova et al., 2020); This variant is associated with the following publications: (PMID: 29038235, 25801821, 28717661, 29753700, 17924555, 26689913, 29922827, 16429406, 29625052, 33050356)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590358	SCV000695431	pathogenic	Fanconi anemia complementation group C	2020-08-10	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.455dupA (p.Asn152LysfsX9) 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 1.6e-05 in 250668 control chromosomes. c.455dupA has been reported in the literature in at-least one individual affected with Fanconi Anemia and has been subsequently cited by others in settings of tumor testing (example, Yates_2006, Ameziane_2008, Pilonetto_2017, Kato_2017, Cheng_2015, Waszak_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 (n=4)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000590358	SCV001163629	pathogenic	Fanconi anemia complementation group C		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022696	SCV001184463	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The c.455dupA pathogenic mutation, located in coding exon 4 of the FANCC gene, results from a duplication of A at nucleotide position 455, causing a translational frameshift with a predicted alternate stop codon (p.N152Kfs*9). This mutation (designated as c.455_456dupA) has been reported in the compound heterozygous state with another FANCC mutation in a patient with Fanconi anemia (Yates J et al. Hum. Mutat. 2006 Feb;27:214). It was also observed in an 11-year-old male with medulloblastoma (Waszak SM et al. Lancet Oncol. 2018 06;19:785-798). 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.
Sema4, Sema4	RCV000465895	SCV002535103	pathogenic	Fanconi anemia	2021-10-18	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000590358	SCV002778817	pathogenic	Fanconi anemia complementation group C	2022-01-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000482020	SCV004032858	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	FANCC: PVS1, PM2
Counsyl	RCV000590358	SCV001132187	likely pathogenic	Fanconi anemia complementation group C	2015-06-03	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000590358	SCV001365294	pathogenic	Fanconi anemia complementation group C	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter.
GenomeConnect - Invitae Patient Insights Network	RCV000590358	SCV001749623	not provided	Fanconi anemia complementation group C		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 08-03-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.