ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6203T>C (p.Met2068Thr) (rs863224547)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197550 SCV000254029 uncertain significance Familial adenomatous polyposis 1 2018-05-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 2068 of the APC protein (p.Met2068Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 216173). 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 threonine 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 RCV000237050 SCV000292794 uncertain significance not provided 2016-02-24 criteria provided, single submitter clinical testing This variant is denoted APC c.6203T>C at the cDNA level, p.Met2068Thr (M2068T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Met2068Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Met2068Thr occurs at a position that is not conserved and is not located in a known functional 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 Met2068Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000771585 SCV000904170 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing

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