ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4766G>A (p.Arg1589His) (rs374048423)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000758729 SCV000149005 uncertain significance not provided 2018-05-11 criteria provided, single submitter clinical testing This variant is denoted APC c.4766G>A at the cDNA level, p.Arg1589His (R1589H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been reported in at least one individual with breast cancer (Tung 2016). APC Arg1589His was not observed in large population cohorts (Lek 2016). APC Arg1589His is located in the SAMP repeats/axin binding domain and the 20-amino acid repeat Beta-catenin down-regulating domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether APC Arg1589His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115096 SCV000217093 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Conflicting evidence
Invitae RCV000475721 SCV000552569 uncertain significance Familial adenomatous polyposis 1 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1589 of the APC protein (p.Arg1589His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs374048423, ExAC 0.002%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 127298). 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 histidine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758729 SCV000887524 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing
Color RCV000115096 SCV000911473 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing

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