ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3743C>T (p.Thr1248Ile) (rs878853441)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226147 SCV000282746 uncertain significance Familial adenomatous polyposis 1 2018-07-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1248 of the APC protein (p.Thr1248Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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: 236594). 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 RCV000479944 SCV000571444 uncertain significance not provided 2016-09-18 criteria provided, single submitter clinical testing This variant is denoted APC c.3743C>T at the cDNA level, p.Thr1248Ile (T1248I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Thr1248Ile 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 Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Thr1248Ile occurs at a position that is not conserved and is located within the Ser-rich region responsible for down-regulation through a process mediated by direct ubiquitination (UniProt). 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 Thr1248Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564682 SCV000667419 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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