ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5684C>T (p.Thr1895Ile)

dbSNP: rs752605851
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000626305 SCV000746966 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing This variant is denoted APC c.5684C>T at the cDNA level, p.Thr1895Ile (T1895I) 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 pathogenic or benign. APC Thr1895Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in 20-aa repeat Beta-catenin down-regulating domain and the SAMP repeats/axin binding 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 Thr1895Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV003653234 SCV002202785 uncertain significance Familial adenomatous polyposis 1 2023-12-15 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1895 of the APC protein (p.Thr1895Ile). This variant is present in population databases (rs752605851, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 523085). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357893 SCV001553492 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The APC p.Thr1895Ile variant was not identified in the literature nor was it identified in the LOVD 3.0, or UMD-LSDB. The variant was identified in dbSNP (ID: rs752605851) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by GeneDx). The variant was identified in control databases in 1 of 245714 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 1 of 30774 chromosomes (freq: 0.00003), but not in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish, populations. The p.Thr1895 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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