ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1642C>T (p.Arg548Ter) (rs104886457)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058924 SCV000211058 pathogenic not provided 2020-08-26 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation as the last 11 amino acids are lost; Published functional studies demonstrate a damaging effect: hypersensitivity to mitomycin C and inability to correct the cellular Fanconi anemia phenotype in transfected cells (Lo ten Foe 1996); Observed in the heterozygous state individuals with breast, gastric, or colon cancer (Slavin 2017, AlDubayan 2018, Drk 2019); This variant is associated with the following publications: (PMID: 12670332, 28139070, 28425259, 8103176, 8844212, 24584348, 20869034, 9207444, 27289500, 26681312, 29025585, 8348157, 17924555, 8882868, 29478780, 31467304, 29625052, 26689913)
Invitae RCV000205197 SCV000261073 pathogenic Fanconi anemia 2020-09-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the FANCC mRNA at codon 548 (p.Arg548*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated FANCC protein lacking the last 11 amino acid residues. This variant is present in population databases (rs104886457, ExAC 0.005%). This variant has been reported as homozygous and in trans with a second loss-of-function variant in individuals affected with Fanconi anemia (PMID: 8103176, 24584348). ClinVar contains an entry for this variant (Variation ID: 12047). An experimental study has shown that this nonsense change renders FANCC unable to correct the hypersensitivity to mitomycin C in a Fanconi anemia cell line (PMID: 8882868), suggesting that the very C-terminal amino acids are critical for proper FANCC function. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515355 SCV000611188 pathogenic Fanconi anemia, complementation group C; Tracheoesophageal fistula 2017-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572840 SCV000673286 pathogenic Hereditary cancer-predisposing syndrome 2019-02-14 criteria provided, single submitter clinical testing The p.R548* pathogenic mutation (also known as c.1642C>T), located in coding exon 14 of the FANCC gene, results from a C to T substitution at nucleotide position 1642. This changes the amino acid from an arginine to a stop codon within coding exon 14. This mutation has been previously described in a compound heterozygous state in two unrelated patients with Fanconi Anemia (FA) (Aftab I et al. Turk. J. Med. Sci. 2017 Apr;47:391-398; Gibson RA et al. Hum. Mutat. 1996;8:140-8). This mutation has also been identified in a heterozygous state in individuals with breast cancer and/or colorectal cancer/polyps (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; AlDubayan SH et al. Am. J. Hum. Genet. 2018 03;102(3):401-414). Functional studies have shown that cells transfected with this alteration are unable to correct the cellular phenotype of FA (Lo ten Foe JR et al. Hum. Genet. 1996 Nov;98:522-3). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000012827 SCV000695427 pathogenic Fanconi anemia, complementation group C 2016-08-31 criteria provided, single submitter clinical testing Variant summary: The c.1642C>T (p.Arg548*) variant in FANCC gene is a nonsense change predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The p.Arg548* is expected to lack last 11 amino acids and was unable to restore MMC hypersensitivity in the functional assay. The variant is present in the large control population dataset of ExAC at a low frequency 0.00002 (3/120522 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.002) in this gene. The variant of interest has been reported in multiple affected individuals in homozygous or compound heterozygous state with a confirmed diagnosis of FA. Per multiple reports, this variant is strongly correlated with increased numbers of severe congenital malformation, earlier onsets of marrow failure, and overall poorer survival rate. In addition, multiple reputable databases/clinical laboratories classified this variant as Pathogenic. Taken together, the variant was classified as Pathogenic.
Mendelics RCV000012827 SCV000838339 pathogenic Fanconi anemia, complementation group C 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000012827 SCV000894483 pathogenic Fanconi anemia, complementation group C 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000205197 SCV000967666 pathogenic Fanconi anemia 2018-05-14 criteria provided, single submitter clinical testing The p.Arg548X variant in FANCC has been identified in the homozygous or compound heterozygous state in more than 9 individuals with Fanconi anemia, and segregat ed with disease in at least 1 affected family member (Murer-Orlando 1993, Gillio 1997, Aftab 2017). This variant has also been identified in 8/111606 European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit; dbSNP rs104886457). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrie r frequency. This nonsense variant leads to a premature termination codon at pos ition 548. This alteration occurs within the last exon and is more likely to esc ape nonsense mediated decay (NMD) and result in a truncated protein. Nevertheles s, in vitro functional studies provide evidence that this variant disrupts FANCC function (Lo Ten Foe 1996). In summary, this variant meets criteria to be class ified as pathogenic for autosomal recessive Fanconi anemia. ACMG/AMP Criteria ap plied: PM3_Very Strong; PM4; PS3_Moderate.
Baylor Genetics RCV000012827 SCV001163620 pathogenic Fanconi anemia, complementation group C criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000012827 SCV001193968 likely pathogenic Fanconi anemia, complementation group C 2019-12-04 criteria provided, single submitter clinical testing NM_000136.2(FANCC):c.1642C>T(R548*) is classified as likely pathogenic in the context of FANCC-related Fanconi anemia. Sources cited for classification include the following: PMID 9207444, 17924555, 8844212, 8882868 and 24469828. Classification of NM_000136.2(FANCC):c.1642C>T(R548*) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000012827 SCV000033067 pathogenic Fanconi anemia, complementation group C 1993-09-11 no assertion criteria provided literature only
GeneReviews RCV000012827 SCV000057805 pathogenic Fanconi anemia, complementation group C 2021-06-01 no assertion criteria provided literature only Common in northern Europeans & southern Italy
SNPedia RCV000058924 SCV000090445 not provided not provided no assertion provided not provided
Leiden Open Variation Database RCV000012827 SCV001365343 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.

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