Submissions for variant NM_006231.4(POLE):c.4427T>G (p.Phe1476Cys)

gnomAD frequency: 0.00001  dbSNP: rs985504177

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003156258	SCV000653287	uncertain significance	not provided	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1476 of the POLE protein (p.Phe1476Cys). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 473663). 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.
Mendelics	RCV003492098	SCV000838688	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002330958	SCV002631182	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	clinical testing	The p.F1476C variant (also known as c.4427T>G), located in coding exon 34 of the POLE gene, results from a T to G substitution at nucleotide position 4427. The phenylalanine at codon 1476 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. 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.
GeneDx	RCV003156258	SCV003845776	uncertain significance	not provided	2022-09-23	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
PreventionGenetics, part of Exact Sciences	RCV004737824	SCV005360228	uncertain significance	POLE-related disorder	2024-08-14	no assertion criteria provided	clinical testing	The POLE c.4427T>G variant is predicted to result in the amino acid substitution p.Phe1476Cys. This variant was reported in an individual with a personal history of colorectal cancer and family history of stomach cancer who also carried a likely causative variant in MSH6 (Table S3, de Oliveira et al. 2022. PubMed ID: 35534704). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/473663/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.