ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.553C>T (p.Arg185Ter) (rs121917783)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115356 SCV000149265 pathogenic not provided 2018-07-26 criteria provided, single submitter clinical testing This variant is denoted FANCC c.553C>T at the cDNA level and p.Arg185Ter (R185X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. In addition to the predicted nonsense variant, RNA analyses have demonstrated that this variant causes partial skipping of exon 7, previously reported as exon 6 using alternate nomenclature (Gibson 1993, Belanger 2013). This variant has been reported in the homozygous and compound heterozygous states in individuals with Fanconi anemia (Gibson 1993, Tsangaris 2011, Gille 2012). This variant has also been identified in the heterozygous state in two sisters with breast cancer, who also had a family history of breast cancer and melanoma (Thompson 2012), and in an individual with prostate cancer who also carried a BRCA2 truncating variant (Annala 2017). We consider this variant to be pathogenic.
Invitae RCV000471314 SCV000549970 pathogenic Fanconi anemia 2018-12-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 185 (p.Arg185*) of the FANCC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121917783, ExAC 0.008%). This variant has been observed as homozygous and as compound heterozygous in individuals with Fanconi anemia (PMID: 7689011, 22778927, 8128956, 17924555, 23613520). In addition, this variant has been observed in several individuals affected with breast and/or ovarian cancer (PMID: 23028338, 26681312). ClinVar contains an entry for this variant (Variation ID: 12044). This nonsense variant has been reported to cause exon 6 skipping in a portion of transcripts by mRNA analysis, resulting in a prematurely truncated protein (p.Met153Asnfs*23) (PMID: 7689011, 20509860). Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000568180 SCV000673288 pathogenic Hereditary cancer-predisposing syndrome 2018-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Integrated Genetics/Laboratory Corporation of America 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.
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.

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