ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3964G>A (p.Glu1322Lys) (rs752926571)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219449 SCV000276920 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
Invitae RCV000465959 SCV000552745 uncertain significance Familial adenomatous polyposis 1 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1322 of the APC protein (p.Glu1322Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs752926571, ExAC 0.006%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 232718). 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 lysine 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.
GeneDx RCV000485020 SCV000569018 uncertain significance not provided 2016-08-03 criteria provided, single submitter clinical testing This variant is denoted APC c.3964G>A at the cDNA level, p.Glu1322Lys (E1322K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Glu1322Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Glu1322Lys occurs at a position that is not conserved and is located in the 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 evidence, it is unclear whether APC Glu1322Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000219449 SCV000909266 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing

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