ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4139C>T (p.Thr1380Ile) (rs876660713)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223239 SCV000278355 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
GeneDx RCV000522947 SCV000618508 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing This variant is denoted APC c.4139C>T at the cDNA level, p.Thr1380Ile (T1380I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported has a somatic variant in a serous endometrial tumor (Castonguay 2014). APC Thr1380Ile was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Thr1380Ile occurs at a position that is conserved across species and is located in within the 20-amino acid repeat beta-catenin down-regulating domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Thr1380Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000557126 SCV000647498 uncertain significance Familial adenomatous polyposis 1 2017-05-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1380 of the APC protein (p.Thr1380Ile). The threonine residue is highly 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 been reported in 2 individuals affected with familial adenomatous polyposis in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 233890). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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