Submissions for variant NM_000038.6(APC):c.3073A>G (p.Ile1025Val)

gnomAD frequency: 0.00001  dbSNP: rs370591349

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159546	SCV000209510	uncertain significance	not provided	2014-10-01	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3073A>G at the cDNA level, p.Ile1025Val (I1025V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ile1025Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Ile1025Val occurs at a position that is conserved across species and is located in a domain responsible for down-regulation through a process mediated by direct ubiquitination (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 Ile1025Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000218802	SCV000275523	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	clinical testing	The p.I1025V variant (also known as c.3073A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 3073. The isoleucine at codon 1025 is replaced by valine, an amino acid with highly similar properties. In one study, this variant was detected in 1/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is highly 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.
Invitae	RCV003743595	SCV000647420	uncertain significance	Familial adenomatous polyposis 1	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1025 of the APC protein (p.Ile1025Val). This variant is present in population databases (rs370591349, gnomAD 0.006%). 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: 181798). 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	RCV000218802	SCV000905974	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 1025 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 APC-related disorders in the literature. This variant has been identified in 2/250952 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.