ClinVar Genomic variation as it relates to human health

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 ute.org; 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.

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.

This sequence change creates a premature translational stop signal (p.Arg548*) in the FANCC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the FANCC protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 8103176, 24584348). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12047). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects FANCC function (PMID: 8882868). For these reasons, this variant has been classified as Pathogenic.

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.

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)

The c.1642C>T;p.(Arg548*) variant creates a premature translational stop signal in the FANCC gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12047) - PS4. The variant is present at low allele frequencies population databases (rs104886457 – gnomAD 0.0004954%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic

The FANCC c.1642C>T (p.Arg548Ter) change is a nonsense variant that is predicted to cause premature protein truncation. The variant is not expected to result in nonsense mediated decay, but functional studies have demonstrated a damaging effect on FANCC function (PMID: 8882868). This variant has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals affected with Fanconi anemia (PMID: 8103176, 28425259, 33960719). It has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic.

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.

Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter.

Common in northern Europeans & southern Italy