ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4082C>T (p.Pro1361Leu) (rs1060503264)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472077 SCV000552468 uncertain significance Familial adenomatous polyposis 1 2018-08-29 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1361 of the APC protein (p.Pro1361Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in the germline of individuals with a APC-related disease. 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000483101 SCV000572072 uncertain significance not provided 2016-10-20 criteria provided, single submitter clinical testing This variant is denoted APC c.4082C>T at the cDNA level, p.Pro1361Leu (P1361L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in soft tissue sarcoma, cutaneous carcinosarcoma, salivary duct carcinoma, esophageal carcinoma, and other cancer tissues (Minde 2011, Gatalica 2014, Ku 2014, Paniz-Mondolfi 2014, COSMIC). APC Pro1361Leu 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 Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Pro1361Leu occurs at a position that is conserved in mammals and is located in the 20-amino acid repeat beta-catenin down-regulating 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 Pro1361Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564035 SCV000667674 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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