ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4408G>C (p.Ala1470Pro) (rs1064795575)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479051 SCV000571515 uncertain significance not provided 2016-08-26 criteria provided, single submitter clinical testing This variant is denoted APC c.4408G>C at the cDNA level, p.Ala1470Pro (A1470P) at the protein level, and results in the change of an Alanine to a Proline (GCT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ala1470Pro 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 Alanine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. APC Ala1470Pro occurs at a position that is not conserved and is located in the 20 amino acid repeat beta-catenin down-regulating domain (Azzopardi 2008)). 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 Ala1470Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000581076 SCV000681663 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-18 criteria provided, single submitter clinical testing
Invitae RCV000646374 SCV000768143 uncertain significance Familial adenomatous polyposis 1 2017-11-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 1470 of the APC protein (p.Ala1470Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. 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: 422126). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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