ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.802T>A (p.Cys268Ser) (rs730881718)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160480 SCV000211045 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing This variant is denoted FANCC c.802T>A at the cDNA level, p.Cys268Ser (C268S) at the protein level, and results in the change of a Cysteine to a Serine (TGT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Cys268Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with Hsp70 and GRP94 (Gordon 2000). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether FANCC Cys268Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000459016 SCV000549960 uncertain significance Fanconi anemia 2018-06-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 268 of the FANCC protein (p.Cys268Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs730881718, ExAC 0.002%) but has not been reported in the literature in individuals with a FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 182479). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The serine 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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