ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1508C>T (p.Thr503Met) (rs779982610)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222127 SCV000278975 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1508C>T at the cDNA level, p.Thr503Met (T503M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as a germline variant. However, it has been reported as a somatic variant in a liver carcinoma cell line (Hudson 2014). FANCC Thr503Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). FANCC Thr503Met is located in the cdc2 interaction domain (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 Thr503Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000799605 SCV000939276 uncertain significance Fanconi anemia 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 503 of the FANCC protein (p.Thr503Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs779982610, ExAC 0.002%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 234312). 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 methionine 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.

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