Submissions for variant NM_006231.4(POLE):c.4736G>A (p.Arg1579His)

gnomAD frequency: 0.00008  dbSNP: rs375590443

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000506949	SCV000289403	uncertain significance	not provided	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1579 of the POLE protein (p.Arg1579His). This variant is present in population databases (rs375590443, gnomAD 0.02%). 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: 240539). 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	RCV000506949	SCV000602057	uncertain significance	not provided	2019-04-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000506949	SCV001801318	uncertain significance	not provided	2024-12-31	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002503911	SCV002809969	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	2022-05-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165636	SCV003894282	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	The c.4736G>A (p.R1579H) alteration is located in exon 37 (coding exon 37) of the POLE gene. This alteration results from a G to A substitution at nucleotide position 4736, causing the arginine (R) at amino acid position 1579 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004532931	SCV004116137	uncertain significance	POLE-related disorder	2022-09-08	criteria provided, single submitter	clinical testing	The POLE c.4736G>A variant is predicted to result in the amino acid substitution p.Arg1579His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133219308-C-T). This change has been documented as a variant of uncertain significance by multiple labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/240539/evidence/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breakthrough Genomics, Breakthrough Genomics	RCV000506949	SCV005192061	uncertain significance	not provided		criteria provided, single submitter	not provided