Submissions for variant NM_000038.6(APC):c.8233C>A (p.Pro2745Thr)

gnomAD frequency: 0.00001  dbSNP: rs587779809

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590739	SCV000149036	uncertain significance	not provided	2016-11-01	criteria provided, single submitter	clinical testing	This variant is denoted APC c.8233C>A at the cDNA level, p.Pro2745Thr (P2745T) at the protein level, and results in the change of a Proline to a Threonine (CCT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Pro2745Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Pro2745Thr occurs at a position that is not conserved and is located in the within EB1 Binding domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether APC Pro2745Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590739	SCV000694137	uncertain significance	not provided	2017-01-10	criteria provided, single submitter	clinical testing	Variant summary: The APC c.8233C>A (p.Pro2745Thr) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121352 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000772716	SCV000905997	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces proline with threonine at codon 2745 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 1/245878 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	RCV003534345	SCV000957753	uncertain significance	Familial adenomatous polyposis 1	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2745 of the APC protein (p.Pro2745Thr). This variant is present in population databases (rs587779809, gnomAD 0.0009%). 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: 127324). 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	RCV000772716	SCV001189846	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-07	criteria provided, single submitter	clinical testing	The p.P2745T variant (also known as c.8233C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 8233. The proline at codon 2745 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is not 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.
Baylor Genetics	RCV002514580	SCV004204586	uncertain significance	Familial adenomatous polyposis 1	2023-06-29	criteria provided, single submitter	clinical testing