Submissions for variant NM_006231.4(POLE):c.5480C>T (p.Ser1827Leu)

gnomAD frequency: 0.00008  dbSNP: rs763031537

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000486309	SCV000543938	uncertain significance	not provided	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1827 of the POLE protein (p.Ser1827Leu). This variant is present in population databases (rs763031537, gnomAD 0.01%). 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: 405627). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. 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.
GeneDx	RCV000486309	SCV000571074	uncertain significance	not provided	2025-01-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with metastatic prostate cancer (PMID: 32923906); This variant is associated with the following publications: (PMID: 25228659, 29625052, 32923906, Krishnan[Abstract])
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486309	SCV001469884	uncertain significance	not provided	2019-09-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000486309	SCV002048032	uncertain significance	not provided	2021-01-25	criteria provided, single submitter	clinical testing	The POLE c.5480C>T; p.Ser1827Leu variant (rs763031537) variant, to our knowledge, is not reported in the medical literature or gene specific databases. The variant is reported in the ClinVar database (Variation ID: 405627) and is reported in the general population with an allele frequency of 0.002% (6/251,440 alleles) in the Genome Aggregation Database. The serine at codon 1827 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.635). This variant is not located in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). However, due to limited information, the significance of the p.Ser1827Leu variant is uncertain at this time. References: Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596183	SCV005090433	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004943847	SCV005479467	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-06	criteria provided, single submitter	clinical testing	The p.S1827L variant (also known as c.5480C>T), located in coding exon 40 of the POLE gene, results from a C to T substitution at nucleotide position 5480. The serine at codon 1827 is replaced by leucine, an amino acid with dissimilar 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004596183	SCV005886685	uncertain significance	not specified	2025-02-04	criteria provided, single submitter	clinical testing	Variant summary: POLE c.5480C>T (p.Ser1827Leu) results in a non-conservative amino acid change located in the DNA polymerase epsilon, catalytic subunit A, C-terminal domain (IPR013697) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251440 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5480C>T has been reported in the literature in at least one individual affected with metastatic prostate cancer without strong evidence for causality (e.g. Boyle_2020). This report does not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32923906). ClinVar contains an entry for this variant (Variation ID: 405627). Based on the evidence outlined above, the variant was classified as uncertain significance.