ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1000C>T (p.Arg334Trp) (rs140348260)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195976 SCV000254248 uncertain significance Fanconi anemia 2019-08-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 334 of the FANCC protein (p.Arg334Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs140348260, ExAC 0.1%). This variant has been reported in an individual affected with prostate cancer (PMID: 26689913). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000486496 SCV000566182 uncertain significance not provided 2018-09-10 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1000C>T at the cDNA level, p.Arg334Trp (R334W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was observed in at least one individual with a personal history of prostate cancer (Lu 2015). FANCC Arg334Trp was observed at an allele frequency of 0.12% (22/18788) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the HSP70 interaction domain (Gordon 2000). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether FANCC Arg334Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001009657 SCV001169750 likely benign Hereditary cancer-predisposing syndrome 2019-10-23 criteria provided, single submitter clinical testing Insufficient evidence

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