Submissions for variant NM_000038.6(APC):c.4898C>T (p.Thr1633Ile)

gnomAD frequency: 0.00001  dbSNP: rs765215625

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485896	SCV000571915	uncertain significance	not provided	2020-09-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of acute myeloid leukemia (Zhang 2015); This variant is associated with the following publications: (PMID: 26580448)
Invitae	RCV003535763	SCV000813268	uncertain significance	Familial adenomatous polyposis 1	2024-01-19	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 1633 of the APC protein (p.Thr1633Ile). This variant is present in population databases (rs765215625, gnomAD 0.01%). This missense change has been observed in individual(s) with acute myeloid leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 422439). 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.
Ambry Genetics	RCV001023216	SCV001185061	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	clinical testing	The p.T1633I variant (also known as c.4898C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 4898. The threonine at codon 1633 is replaced by isoleucine, an amino acid with similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole-exome sequencing; this patient was diagnosed with acute myeloid leukemia (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192985	SCV001361483	uncertain significance	not specified	2019-10-24	criteria provided, single submitter	clinical testing	Variant summary: APC c.4898C>T (p.Thr1633Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251208 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4898C>T has been reported in the literature in one individual affected with AML as a germline variant (Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000685771	SCV001775529	uncertain significance	Familial adenomatous polyposis 1	2021-08-03	criteria provided, single submitter	clinical testing