ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.823T>C (p.Phe275Leu) (rs745621828)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204906 SCV000260011 uncertain significance Fanconi anemia 2015-08-19 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 275 of the FANCC protein (p.Phe275Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (<0.01%) and has been identified in a patient with pancreatic cancer (PMID: 15695377). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000485118 SCV000566691 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted FANCC c.823T>C at the cDNA level, p.Phe275Leu (F275L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>CTT). Also reported as FANCC 1078T>C using alternate nomenclature, this variant has been observed in at least one individual with pancreatic cancer (Couch 2005). FANCC Phe275Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the GRP94 and HSP90 interaction domains (Gordon 2000). In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether FANCC Phe275Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572325 SCV000673300 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient evidence

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