ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5302A>G (p.Lys1768Glu) (rs199630012)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766438 SCV000149011 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing This variant is denoted APC c.5302A>G at the cDNA level, p.Lys1768Glu (K1768E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. APC Lys1768Glu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Lys1768Glu occurs at a position that is not conserved and is located in the 20-amino acid repeat beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether APC Lys1768Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115102 SCV000186217 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000411965 SCV000489362 uncertain significance Familial adenomatous polyposis 1 2016-09-27 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000211921 SCV000591190 uncertain significance not specified 2014-03-24 criteria provided, single submitter clinical testing
Invitae RCV000411965 SCV000647573 uncertain significance Familial adenomatous polyposis 1 2017-06-06 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1768 of the APC protein (p.Lys1768Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs199630012, ExAC 0.003%). This variant has not been reported in the literature in individuals with an APC-related disease. ClinVar contains an entry for this variant (Variation ID: 127304). 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 glutamic acid 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, this variant has uncertain impact on APC function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000115102 SCV000687013 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-24 criteria provided, single submitter clinical testing

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