ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5399A>G (p.Asn1800Ser) (rs865782682)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221421 SCV000277891 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
Illumina Clinical Services Laboratory,Illumina RCV000301591 SCV000452026 uncertain significance APC-Associated Polyposis Disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000485570 SCV000569007 uncertain significance not provided 2018-10-12 criteria provided, single submitter clinical testing This variant is denoted APC c.5399A>G at the cDNA level, p.Asn1800Ser (N1800S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asn1800Ser was not observed in large population cohorts (Lek 2016). This variant is located in the 20-aa repeat Beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Asn1800Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000692047 SCV000819854 uncertain significance Familial adenomatous polyposis 1 2019-10-07 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1800 of the APC protein (p.Asn1800Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. 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: 233507). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485570 SCV000887537 uncertain significance not provided 2017-12-02 criteria provided, single submitter clinical testing
Color RCV000221421 SCV000911031 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-23 criteria provided, single submitter clinical testing

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