ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4594G>A (p.Asp1532Asn) (rs730881251)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159556 SCV000209527 uncertain significance not provided 2014-09-02 criteria provided, single submitter clinical testing This variant is denoted APC c.4594G>A at the cDNA level, p.Asp1532Asn (D1532N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asp1532Asn 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 Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Asp1532Asn occurs at a position that is highly conserved through mammals and is located in a Serine rich domain involved in beta-catenin downregulation (UniProt, Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Asp1532Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000291608 SCV000452014 uncertain significance APC-Associated Polyposis Disorders 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563203 SCV000667548 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000810645 SCV000950867 uncertain significance Familial adenomatous polyposis 1 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1532 of the APC protein (p.Asp1532Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 181807). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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