Submissions for variant NM_000038.6(APC):c.4900C>G (p.Pro1634Ala)

dbSNP: rs587779795

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115098	SCV000149007	uncertain significance	not provided	2017-12-18	criteria provided, single submitter	clinical testing	This variant is denoted APC c.4900C>G at the cDNA level, p.Pro1634Ala (P1634A) at the protein level, and results in the change of a Proline to an Alanine (CCG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Pro1634Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Pro1634Ala is located within the 20 amino acid 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 Pro1634Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000583465	SCV000686991	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 1634 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 1/251204 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.
Invitae	RCV003534338	SCV000822381	uncertain significance	Familial adenomatous polyposis 1	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1634 of the APC protein (p.Pro1634Ala). This variant is present in population databases (rs587779795, gnomAD no frequency). 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: 127300). 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. 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	RCV000583465	SCV001185083	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	The p.P1634A variant (also known as c.4900C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 4900. The proline at codon 1634 is replaced by alanine, an amino acid with highly similar properties. 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.