ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3912A>G (p.Ile1304Met)

dbSNP: rs1064795120
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486168 SCV000570610 uncertain significance not provided 2016-06-07 criteria provided, single submitter clinical testing This variant is denoted APC c.3912A>G at the cDNA level, p.Ile1304Met (I1304M) 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 Ile1304Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. APC Ile1304Met occurs at a position that is not conserved and is located in the 20-amino acid repeat b-catenin down-regulating domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Ile1304Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV003766691 SCV002275943 uncertain significance Familial adenomatous polyposis 1 2022-01-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1304 of the APC protein (p.Ile1304Met). 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. 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. ClinVar contains an entry for this variant (Variation ID: 421415). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency).

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