Submissions for variant NM_000136.3(FANCC):c.553C>T (p.Arg185Ter)

gnomAD frequency: 0.00011  dbSNP: rs121917783

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115356	SCV000149265	pathogenic	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Gibson 1993, Belanger 2013); Published functional studies demonstrate a damaging effect: skipping of the in-frame exon 7, impaired protein migration, and reduced ability to repair DNA interstrand crosslinks (Gibson 1993, Belanger 2013); Observed in the homozygous and compound heterozygous state in patients with Fanconi anemia in published literature (Gibson 1993, Tsangaris 2011, Gille 2012); Observed in the heterozygous state in individuals with FANCC-related cancers (Thompson 2012, Schrader 2016, Melloni 2017, Dork 2019); This variant is associated with the following publications: (PMID: 25525159, 12670332, 21659346, 23028338, 28259476, 26681312, 29416752, 26689913, 20509860, 22778927, 27577878, 30322717, 28125078, 7746424, 26556299, 31467304, 28569218, 7689011, 29625052, 32885271, 32427313)
Invitae	RCV000471314	SCV000549970	pathogenic	Fanconi anemia	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg185*) in the FANCC gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs121917783, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with breast and/or ovarian cancer and Fanconi anemia (PMID: 7689011, 8128956, 17924555, 22778927, 23028338, 23613520, 26681312). ClinVar contains an entry for this variant (Variation ID: 12044). Studies have shown that this premature translational stop signal results in skipping of 7, but is expected to preserve the integrity of the reading-frame (PMID: 7689011, 20509860). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000568180	SCV000673288	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	clinical testing	The p.R185* pathogenic mutation (also known as c.553C>T), located in coding exon 6 of the FANCC gene, results from a C to T substitution at nucleotide position 553. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation has been identified homozygous and compound heterozygous in several Fanconi anemia cohorts (Gibson RA et al. Hum. Mol. Genet. 1993 Jun;2:797-9; Ameziane N et al. Hum. Mutat. 2008 Jan;29:159-66; Gille JJ et al. Anemia. 2012 Jun;2012:603253; Tsangaris E et al. J. Med. Genet. 2011 Sep;48:618-28) and was not detected in 70 unrelated British controls (Gibson RA et al. Hum. Mol. Genet. 1993 Jun;2:797-9). This mutation has also been reported in individuals with breast cancer and a family history of breast and/or ovarian cancer (Thompson ER et al. PLoS Genet. 2012 Sep;8:e1002894; Susswein LR et al. Genet. Med. 2016 08;18:823-32). Of note, this alteration is also designated as 808C>T in published literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012824	SCV000695434	pathogenic	Fanconi anemia complementation group C	2017-04-03	criteria provided, single submitter	clinical testing	Variant summary: The FANCC c.553C>T (p.Arg185X) variant involves the alteration of a non-conserved nucleotide, resulting in a nonsense codon. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000414 (5/120748 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic FANCC variant (0.0017678). Several reports in the literature have detected the variant among individuals diagnosed with a variety of cancers, including 2 families where the variant segregated with disease in 4 individuals (Verlander_AJHG_1994). Functional studies have revealed that the variant causes partial skip of exon 6 and is predicted to result in frameshit in cell culture via cDNA analysis (Palagyi_MC_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV000012824	SCV001163624	pathogenic	Fanconi anemia complementation group C		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000012824	SCV002777446	pathogenic	Fanconi anemia complementation group C	2021-07-06	criteria provided, single submitter	clinical testing
OMIM	RCV000012824	SCV000033064	pathogenic	Fanconi anemia complementation group C	2015-06-15	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000115356	SCV000607026	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000471314	SCV001190681	pathogenic	Fanconi anemia	2019-05-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356657	SCV001551887	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC p.Arg185* variant was identified in 8 of 20760 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer or as co-occurring with a pathogenic variant in FANCC in compound heterozygous individuals with Fanconi anemia (Ameziane 2008, Chandasekharappa 2013, Gille 2012, Susswein 2015, Thompson 2012, Verlander 1994). The variant was also identified in dbSNP (ID: rs121917783) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, and two other clinical laboratories), and LOVD 3.0 (18x). The variant was not identified in the Cosmic database. The variant was identified in control databases in 19 of 277128 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 17 of 126654 chromosomes (freq: 0.0001), African in 1 of 24014 chromosomes (freq: 0.00004), and South Asian in 1 of 30778 chromosomes (freq: 0.00003), but not in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg185* variant leads to a premature stop codon at position 185, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the FANCC gene are an established mechanism of disease in FANCC-associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.