Submissions for variant NM_006231.4(POLE):c.5792C>T (p.Ser1931Phe)

dbSNP: rs879254232

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236186	SCV000293918	uncertain significance	not provided	2016-02-05	criteria provided, single submitter	clinical testing	This variant is denoted POLE c.5792C>T at the cDNA level, p.Ser1931Phe (S1931F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Ser1931Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLE Ser1931Phe occurs at a position that is not conserved and is not located in a known functional domain (Tahirov 2009, Preston 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLE Ser1931Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000236186	SCV000543913	uncertain significance	not provided	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1931 of the POLE protein (p.Ser1931Phe). This variant is not present in population databases (gnomAD no frequency). 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: 246386). 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.
Ambry Genetics	RCV002356323	SCV002653061	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-16	criteria provided, single submitter	clinical testing	The p.S1931F variant (also known as c.5792C>T), located in coding exon 42 of the POLE gene, results from a C to T substitution at nucleotide position 5792. The serine at codon 1931 is replaced by phenylalanine, 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.