ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6896C>T (p.Pro2299Leu) (rs876658800)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216868 SCV000274509 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000758739 SCV000292766 uncertain significance not provided 2015-11-12 criteria provided, single submitter clinical testing This variant is denoted APC c.6896C>T at the cDNA level, p.Pro2299Leu (P2299L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Pro2299Leu 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 Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Pro2299Leu occurs at a position that is not conserved and is located within a Serine-rich region and within the Basic domain (Azzopardi 2008, UniProt). 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 Pro2299Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000553131 SCV000647678 uncertain significance Familial adenomatous polyposis 1 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2299 of the APC protein (p.Pro2299Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. 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: 230835). 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: "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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758739 SCV000887547 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing
Color RCV000216868 SCV000904769 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-19 criteria provided, single submitter clinical testing

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