Submissions for variant NM_006231.4(POLE):c.1055A>C (p.Gln352Pro)

gnomAD frequency: 0.00002  dbSNP: rs766094330

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409472	SCV000489529	uncertain significance	Colorectal cancer, susceptibility to, 12	2016-10-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000485801	SCV000543962	uncertain significance	not provided	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 352 of the POLE protein (p.Gln352Pro). This variant is present in population databases (rs766094330, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer and malignant melanoma (PMID: 25559809, 26251183). ClinVar contains an entry for this variant (Variation ID: 372024). 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 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.
GeneDx	RCV000485801	SCV000573000	uncertain significance	not provided	2019-11-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with colorectal cancer or melanoma (Aoude 2015, Chubb 2015); This variant is associated with the following publications: (PMID: 31034466, 26251183, 25559809, 2559809)
Ambry Genetics	RCV000570436	SCV000676249	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-28	criteria provided, single submitter	clinical testing	The p.Q352P variant (also known as c.1055A>C), located in coding exon 11 of the POLE gene, results from an A to C substitution at nucleotide position 1055. The glutamine at codon 352 is replaced by proline, an amino acid with similar properties. This variant has been reported in 1/1243 individuals with cutaneous melanoma who underwent targeted sequencing of the POLE gene (Aoude LG et al. Fam. Cancer. 2015 Dec;14:621-8). This alteration has also been identified in an individual with colorectal cancer (Chubb D et al. J. Clin. Oncol. 2015 Feb;33(5):426-32). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000409472	SCV004018529	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-04-19	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000409472	SCV004203554	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-06-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485801	SCV004219070	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with melanoma and colorectal cancer (PMIDs: 26251183 (2015) and 25559809 (2015)). The frequency of this variant in the general population, 0.000035 (4/113762 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493566	SCV004243524	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000485801	SCV005197243	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing