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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