ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6782C>T (p.Pro2261Leu) (rs376494248)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130294 SCV000185142 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000255155 SCV000321404 uncertain significance not provided 2017-10-06 criteria provided, single submitter clinical testing This variant is denoted APC c.6782C>T at the cDNA level, p.Pro2261Leu (P2261L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant was observed in at least one individual with colon cancer and one individual with advanced cancer, undergoing multi-gene panel testing (Pearlman 2016, Mandelker 2017). APC Pro2261Leu was observed at an allele frequency of 0.07% (17/24024) in individuals of African ancestry in large population cohorts (Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Pro2261Leu occurs a position that is conserved across species and is located within the basic domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Pro2261Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000410458 SCV000487801 uncertain significance Familial adenomatous polyposis 1 2015-12-01 criteria provided, single submitter clinical testing
Invitae RCV000410458 SCV000647667 uncertain significance Familial adenomatous polyposis 1 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2261 of the APC protein (p.Pro2261Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs376494248, ExAC 0.05%). This variant has been reported in an individual affected with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 141681). 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: "Probably Damaging"; Align-GVGD: "Class C15"). 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 RCV000130294 SCV000681825 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Mendelics RCV000410458 SCV000838142 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing

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