ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.532G>A (p.Glu178Lys) (rs554302947)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482270 SCV000572289 uncertain significance not provided 2016-11-14 criteria provided, single submitter clinical testing This variant is denoted FANCC c.532G>A at the cDNA level, p.Glu178Lys (E178K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. However, it has been reported in the literature in an acute myeloid leukemia sample (Lu 2015). FANCC Glu178Lys was not observed at a significant allele frequency in 1000 Genomes. Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FANCC Glu178Lys occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located within the region of interaction with GRP94 and Hsp70 (Gordon 2000). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether FANCC Glu178Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000548500 SCV000626252 uncertain significance Fanconi anemia 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 178 of the FANCC protein (p.Glu178Lys). 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 (rs554302947, ExAC 0.01%) but has not been reported in the literature in individuals with a FANCC-related disease. 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on 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.
Ambry Genetics RCV001023937 SCV001185881 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-15 criteria provided, single submitter clinical testing Insufficient evidence

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