ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7778A>G (p.Asn2593Ser) (rs367676584)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215340 SCV000278393 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000458485 SCV000552615 uncertain significance Familial adenomatous polyposis 1 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 2593 of the APC protein (p.Asn2593Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs367676584, ExAC 0.003%). This variant has been reported in an individual affected with colorectal adenomas (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 161205). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000483957 SCV000564584 uncertain significance not provided 2018-01-24 criteria provided, single submitter clinical testing This variant is denoted APC c.7778A>G at the cDNA level, p.Asn2593Ser (N2593S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant was observed in one individual with fewer than 10 colorectal adenomas (Azzopardi 2008). APC Asn2593Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the EB1 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 Asn2593Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000215340 SCV000904043 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148361 SCV000190051 likely benign Colorectal adenoma 2014-06-01 no assertion criteria provided research

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