ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1595G>A (p.Arg532Lys) (rs55939573)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199976 SCV000254256 uncertain significance Fanconi anemia 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 532 of the FANCC protein (p.Arg532Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs55939573, ExAC 0.07%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 216285). 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, 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.
GeneDx RCV000520121 SCV000618137 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1595G>A at the cDNA level, p.Arg532Lys (R532K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. FANCC Arg532Lys was observed at an allele frequency of 0.09% (16/17,244) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the cdc2 binding 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 Arg532Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001012322 SCV001172755 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-14 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV001167954 SCV001330505 uncertain significance Fanconi anemia, complementation group C 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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