ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1606G>A (p.Glu536Lys) (rs138098808)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199835 SCV000253990 uncertain significance Familial adenomatous polyposis 1 2019-01-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 536 of the APC protein (p.Glu536Lys). 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 (rs138098808, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with colon cancer and suspected Lynch syndrome (PMID: 27978560, 25980754). ClinVar contains an entry for this variant (Variation ID: 216151). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000217491 SCV000273018 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000656746 SCV000292449 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing This variant is denoted APC c.1606G>A at the cDNA level, p.Glu536Lys (E536K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has been reported in an individual with colon cancer, a patient with a personal history of a Lynch syndrome-associated cancer and/or polyps, and in two individuals with breast cancer (Tung 2015, Yurgelun 2015, Pearlman 2017). APC Glu536Lys was observed at an allele frequency of 0.08% (20/24,026 alleles) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located within the armadillo region (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether APC Glu536Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235744 SCV000600046 uncertain significance not specified 2017-06-09 criteria provided, single submitter clinical testing
Color RCV000217491 SCV000681478 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing
Mendelics RCV000199835 SCV000838079 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764561 SCV000895649 uncertain significance Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing

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