ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6637A>G (p.Met2213Val) (rs186926737)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130848 SCV000185746 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000236813 SCV000292751 uncertain significance not provided 2018-09-21 criteria provided, single submitter clinical testing This variant is denoted APC c.6637A>G at the cDNA level, p.Met2213Val (M2213V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant was observed in an individual with either a Lynch syndrome-associated cancer and/or colorectal polyps (Yurgelun 2015). APC Met2213Val was observed at an allele frequency of 0.05% (12/23990) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located within the basic domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Met2213Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000409644 SCV000488390 uncertain significance Familial adenomatous polyposis 1 2016-03-17 criteria provided, single submitter clinical testing
Invitae RCV000409644 SCV000552775 uncertain significance Familial adenomatous polyposis 1 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 2213 of the APC protein (p.Met2213Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs186926737, ExAC 0.04%). This variant has been reported in an individual undergoing testing for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 142044). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Color RCV000130848 SCV000681811 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing

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