Submissions for variant NM_000038.6(APC):c.44C>T (p.Ala15Val)

dbSNP: rs1064793466

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485888	SCV000566193	uncertain significance	not provided	2015-04-06	criteria provided, single submitter	clinical testing	This variant is denoted APC c.44C>T at the cDNA level, p.Ala15Val (A15V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ala15Val 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Ala15Val occurs at a position that is conserved across species and is located within the oligomerization domain (Azzopardi 2008). Protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Multiple splicing models predict gain of a cryptic splice donor site upstream of the natural site; however these models predict no change to the natural splice donor site. In the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether APC Ala15Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004568153	SCV003343475	uncertain significance	Familial adenomatous polyposis 1	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 15 of the APC protein (p.Ala15Val). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 418836). 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	RCV003298544	SCV004005095	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	The p.A15V variant (also known as c.44C>T), located in coding exon 1 of the APC gene, results from a C to T substitution at nucleotide position 44. The alanine at codon 15 is replaced by valine, an amino acid with similar properties. This amino acid position is well 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.