ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1249G>A (p.Glu417Lys) (rs140687953)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160486 SCV000211051 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1249G>A at the cDNA level, p.Glu417Lys (E417K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. FANCC Glu417Lys was observed at an allele frequency of 0.021% (5/24,026) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located within the region of interaction with Hsp70 (Gordon 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 Glu417Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000477242 SCV000549948 uncertain significance Fanconi anemia 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 417 of the FANCC protein (p.Glu417Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs140687953, ExAC 0.04%). This variant has been reported in a family affected with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 182485). 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, 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.
Ambry Genetics RCV000570128 SCV000673337 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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