ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4597A>G (p.Asn1533Asp) (rs730881226)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159513 SCV000209468 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing This variant is denoted APC c.4597A>G at the cDNA level, p.Asn1533Asp (N1533D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asn1533Asp was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. APC Asn1533Asp occurs at a position that is not conserved and is located in 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 information, it is unclear whether APC Asn1533Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000583326 SCV000686979 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Invitae RCV000813183 SCV000953528 uncertain significance Familial adenomatous polyposis 1 2018-07-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 1533 of the APC protein (p.Asn1533Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. 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: 181772). 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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