ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.767A>G (p.His256Arg) (rs730881716)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000513268 SCV000211042 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing This variant is denoted FANCC c.767A>G at the cDNA level, p.His256Arg (H256R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant was identified in individuals with breast or pancreatic cancer, but was also observed in a healthy control (Couch 2005, Lu 2015, Shindo 2017). FANCC His256Arg was observed at an allele frequency of 0.02% (20/126,702) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located within the binding region with GRP94 and Hsp70 (Gordon & Buchwald 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 His256Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205450 SCV000260164 uncertain significance Fanconi anemia 2018-11-25 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 256 of the FANCC protein (p.His256Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs730881716, ExAC 0.02%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 182476). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513268 SCV000609343 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571601 SCV000673323 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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