ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6196A>G (p.Arg2066Gly) (rs786204043)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167881 SCV000218527 uncertain significance Familial adenomatous polyposis 1 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 2066 of the APC protein (p.Arg2066Gly). The arginine  residue is highly conserved and there is a moderate physicochemical difference between arginine  and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in one individual affected with colorectal cancer (PMID: 18199528). 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; MutationTaster: polymorphism; Align-GVGD:C0). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000483290 SCV000568282 uncertain significance not specified 2017-05-30 criteria provided, single submitter clinical testing This variant is denoted APC c.6196A>G at the cDNA level, p.Arg2066Gly (R2066G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant was identified in 1/691 individuals with an undefined number of colorectal adenomas and was absent in 969 healthy matched controls (Azzopardi 2008). APC Arg2066Gly 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 Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Arg2066Gly occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located within the Ser-rich domain (UniProt). 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 APC Arg2066Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000167881 SCV000784998 uncertain significance Familial adenomatous polyposis 1 2017-03-06 criteria provided, single submitter clinical testing

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