Submissions for variant NM_006231.4(POLE):c.1346C>T (p.Thr449Met)

gnomAD frequency: 0.00001  dbSNP: rs780299012

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001284685	SCV000544111	uncertain significance	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 449 of the POLE protein (p.Thr449Met). This variant is present in population databases (rs780299012, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 34549727). ClinVar contains an entry for this variant (Variation ID: 405790). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. 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	RCV000570912	SCV000671654	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-01	criteria provided, single submitter	clinical testing	The p.T449M variant (also known as c.1346C>T), located in coding exon 13 of the POLE gene, results from a C to T substitution at nucleotide position 1346. The threonine at codon 449 is replaced by methionine, an amino acid with similar properties. This alteration was detected in an individual with a personal and family history of colorectal cancer who underwent whole-exome sequencing (Xu P et al. JCI Insight, 2021 09;6). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284685	SCV001470613	uncertain significance	not provided	2024-06-27	criteria provided, single submitter	clinical testing	The POLE c.1346C>T (p.Thr449Met) variant has been reported in the published literature in an individual with a personal and family history of colorectal cancer (PMID: 34549727 (2021)). The frequency of this variant in the general population, 0.000098 (3/30616 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV001284685	SCV001816503	uncertain significance	not provided	2023-11-21	criteria provided, single submitter	clinical testing	Observed in two individuals with colorectal cancer, one of whom also harbored a germline MSH2 pathogenic variant (PMID: 34549727, 29596542); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29056344, 34549727, 29596542)
Baylor Genetics	RCV004567963	SCV005056536	uncertain significance	Colorectal cancer, susceptibility to, 12	2024-03-22	criteria provided, single submitter	clinical testing
Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine.	RCV001543612	SCV001754763	likely pathogenic	Colorectal cancer	2021-07-19	no assertion criteria provided	research	The Thr449Met variant in POLE has been reported in 1 Chinese family with autosomal dominant predisposition in familial colorectal cancer (CRC).