ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1406C>T (p.Thr469Met) (rs149917017)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487102 SCV000566574 uncertain significance not provided 2018-01-12 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1406C>T at the cDNA level, p.Thr469Met (T469M) 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 pathogenic or benign. FANCC Thr469Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FANCC Thr469Met occurs at a position that is not conserved and is not located in a known functional domain (Gordon 2000). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether FANCC Thr469Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Mendelics RCV000988195 SCV001137832 uncertain significance Fanconi anemia, complementation group A 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001011411 SCV001171729 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-18 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001247526 SCV001420953 uncertain significance Fanconi anemia 2019-04-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 469 of the FANCC protein (p.Thr469Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs149917017, ExAC 0.03%). This variant has not been reported in the literature in individuals with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 419042). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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