ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3227C>G (p.Pro1076Arg) (rs766394131)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484279 SCV000569908 uncertain significance not provided 2016-04-07 criteria provided, single submitter clinical testing This variant is denoted APC c.3227C>G at the cDNA level, p.Pro1076Arg (P1076R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Pro1076Arg 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 Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Pro1076Arg occurs at a position that is not conserved and is located in the 15-amino acid repeat beta-catenin binding domain, within a Ser-rich region and within a region responsible for down-regulation through a process mediated by direct ubiquination (Azzopardi 2008, 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 Pro1076Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000536681 SCV000647436 uncertain significance Familial adenomatous polyposis 1 2018-08-17 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 1076 of the APC protein (p.Pro1076Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline 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: 420886). 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: "Tolerated"; PolyPhen-2: "Possibly 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 RCV000583558 SCV000686928 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-18 criteria provided, single submitter clinical testing

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