ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5072C>T (p.Pro1691Leu) (rs1060503346)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461777 SCV000552716 uncertain significance Familial adenomatous polyposis 1 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1691 of the APC protein (p.Pro1691Leu). 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 individuals with an 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 RCV000480116 SCV000567574 uncertain significance not provided 2015-08-07 criteria provided, single submitter clinical testing This variant is denoted APC c.5072C>T at the cDNA level, p.Pro1691Leu (P1691L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). Although this variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism it was observed as a somatic change in two individuals with cutaneous squamous cell carcinoma (Li 2015). APC Pro1691Leu 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 Pro1691Leu occurs at a position that is conserved in mammals and is located within the 20-amino acid repeat B-catenin down-regulating domain and the SAMP repeats/axin binding 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 Pro1691Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.

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