Submissions for variant NM_000038.6(APC):c.7583T>C (p.Ile2528Thr)

dbSNP: rs730881264

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159575	SCV000209551	uncertain significance	not provided	2014-08-20	criteria provided, single submitter	clinical testing	This variant is denoted APC c.7583T>C at the cDNA level, p.Ile2528Thr (I2528T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ile2528Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Ile2528Thr occurs at a position that is highly conserved through vertebrates and is located in a Ser-rich region (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Ile2528Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003462065	SCV000647720	uncertain significance	Familial adenomatous polyposis 1	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2528 of the APC protein (p.Ile2528Thr). This variant is present in population databases (rs730881264, gnomAD 0.003%). This missense change has been observed in individual(s) with biliary tract cancer (PMID: 36243179). ClinVar contains an entry for this variant (Variation ID: 181823). 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.
Color Diagnostics, LLC DBA Color Health	RCV000581384	SCV000687132	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-06	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 2528 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250780 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000159575	SCV002010857	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000581384	SCV002668659	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	The p.I2528T variant (also known as c.7583T>C), located in coding exon 15 of the APC gene, results from a T to C substitution at nucleotide position 7583. The isoleucine at codon 2528 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003462065	SCV004205242	uncertain significance	Familial adenomatous polyposis 1	2023-08-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004804678	SCV005425011	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 2528 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250780 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV005031672	SCV005667893	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2024-05-15	criteria provided, single submitter	clinical testing