Submissions for variant NM_006231.4(POLE):c.823G>C (p.Asp275His)

dbSNP: rs879254218

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236118	SCV000293866	uncertain significance	not provided	2016-01-26	criteria provided, single submitter	clinical testing	This variant is denoted POLE c.823G>C at the cDNA level, p.Asp275His (D275H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign, although the Asp275 residue has been identified as important for metal ion binding, a necessary step in the catalytic reaction required for exonuclease activity (Derbyshire 1988). Functional assays interrogating a double mutant including a different amino acid alteration at this residue, POLE Asp275Ala, in combination with Glu277Ala, found significantly increased spontaneous mutation rates and loss of exonuclease activity when introduced in human and mouse cells as well as yeast and E. coli (Morrison 1991, Albertson 2009, Agbor 2013). Additionally the prokaryotic corollary of Asp275Ala demonstrated similar results when analyzed in the Phi-29 phage (Bernad 1989). However, to our knowledge, such functional studies have not been performed to interrogate POLE Asp275His.POLE Asp275His 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 Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLE Asp275His occurs at a position that is conserved across species and is located within motif I of the exonuclease domain (Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Although this variant occurs at a residue likely to be functionally important, based on currently available evidence we consider POLE Asp275His to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000236118	SCV000653481	uncertain significance	not provided	2022-03-15	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 246352). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 275 of the POLE protein (p.Asp275His).
Ambry Genetics	RCV003372662	SCV004097430	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-08	criteria provided, single submitter	clinical testing	The p.D275H variant (also known as c.823G>C), located in coding exon 9 of the POLE gene, results from a G to C substitution at nucleotide position 823. The aspartic acid at codon 275 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004737390	SCV005341859	uncertain significance	POLE-related disorder	2024-03-29	no assertion criteria provided	clinical testing	The POLE c.823G>C variant is predicted to result in the amino acid substitution p.Asp275His. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/246352/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.