Submissions for variant NM_006231.4(POLE):c.3716A>G (p.Gln1239Arg)

gnomAD frequency: 0.00016  dbSNP: rs146210785

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484289	SCV000569141	uncertain significance	not provided	2023-03-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Shah2022[Preprint])
Labcorp Genetics (formerly Invitae), Labcorp	RCV000484289	SCV000653233	uncertain significance	not provided	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1239 of the POLE protein (p.Gln1239Arg). This variant is present in population databases (rs146210785, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 420338). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484289	SCV000889745	uncertain significance	not provided	2017-11-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257763	SCV002536821	likely benign	Hereditary cancer-predisposing syndrome	2021-02-23	criteria provided, single submitter	curation
Ambry Genetics	RCV002257763	SCV003745292	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-08	criteria provided, single submitter	clinical testing	The p.Q1239R variant (also known as c.3716A>G), located in coding exon 30 of the POLE gene, results from an A to G substitution at nucleotide position 3716. The glutamine at codon 1239 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005004182	SCV005633722	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	2024-01-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535512	SCV004725265	uncertain significance	POLE-related disorder	2024-02-15	no assertion criteria provided	clinical testing	The POLE c.3716A>G variant is predicted to result in the amino acid substitution p.Gln1239Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD, and it has conflicting interpretations in ClinVar including likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/420338/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.