ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6249A>G (p.Ile2083Met) (rs374625279)

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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 RCV000131598 SCV000186612 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000469492 SCV000552705 uncertain significance Familial adenomatous polyposis 1 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 2083 of the APC protein (p.Ile2083Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. 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: 142466). 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.
GeneDx RCV000759439 SCV000564579 uncertain significance not provided 2015-02-20 criteria provided, single submitter clinical testing This variant is denoted APC c.6249A>G at the cDNA level, p.Ile2083Met (I2083M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATA>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ile2083Met was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. APC Ile2083Met occurs at a position that is moderately conserved among mammals and is not located in a known functional domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Ile2083Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000131598 SCV000681791 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759439 SCV000888759 uncertain significance not provided 2017-12-26 criteria provided, single submitter clinical testing

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