ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3607G>C (p.Gly1203Arg) (rs1057518472)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465493 SCV000552642 uncertain significance Familial adenomatous polyposis 1 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1203 of the APC protein (p.Gly1203Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411470). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
GeneDx RCV000479172 SCV000564571 uncertain significance not provided 2015-03-01 criteria provided, single submitter clinical testing This variant is denoted APC c.3607G>C at the cDNA level, p.Gly1203Arg (G1203R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Gly1203Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Gly1203Arg occurs at a position that is poorly conserved across species and is located in a region predicted to be responsible for protein downregulation by ubiquitination (UniProt) but does not fall into any known functional 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 Gly1203Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568797 SCV000667552 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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