ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5083A>G (p.Arg1695Gly) (rs555019540)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460729 SCV000552604 uncertain significance Familial adenomatous polyposis 1 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1695 of the APC protein (p.Arg1695Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs555019540, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411445). 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: "Benign"; 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 RCV000483622 SCV000565869 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing This variant is denoted APC c.5083A>G at the cDNA level, p.Arg1695Gly (R1695G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Arg1695Gly was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Arg1695Gly occurs at a position that is conserved through mammals and is located in the beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Arg1695Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572779 SCV000667484 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000572779 SCV000681705 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-18 criteria provided, single submitter clinical testing

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