ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1392T>A (p.His464Gln)

dbSNP: rs1057524073
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484950 SCV000573286 uncertain significance not provided 2017-02-09 criteria provided, single submitter clinical testing This variant is denoted APC c.1392T>A at the cDNA level, p.His464Gln (H464Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAT>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC His464Gln 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 Histidine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. APC His464Gln occurs at a position that is conserved across species and is located within the Armadillo region (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 His464Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000775791 SCV000910241 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-03 criteria provided, single submitter clinical testing
Invitae RCV002525936 SCV001558581 uncertain significance Familial adenomatous polyposis 1 2022-05-28 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 464 of the APC protein (p.His464Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 423573). 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: "Benign"; 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.
Ambry Genetics RCV000775791 SCV002696151 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-30 criteria provided, single submitter clinical testing The p.H464Q variant (also known as c.1392T>A), located in coding exon 10 of the APC gene, results from a T to A substitution at nucleotide position 1392. The histidine at codon 464 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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