ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1867C>T (p.Arg623Trp) (rs730881238)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000581316 SCV000209497 uncertain significance not provided 2018-11-24 criteria provided, single submitter clinical testing This variant is denoted APC c.1867C>T at the cDNA level, p.Arg623Trp (R623W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Arg623Trp 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 Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Arg623Trp occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the 4th armadillo repeat (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Arg623Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000460574 SCV000552475 uncertain significance Familial adenomatous polyposis 1 2017-07-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 623 of the APC protein (p.Arg623Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs730881238, ExAC 0.001%). This variant has not been reported in the literature in individuals with APC-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: "Deleterious"; 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.
Color RCV000772640 SCV000905883 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000581316 SCV000691720 likely pathogenic not provided no assertion criteria provided clinical testing

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