Submissions for variant NM_006231.4(POLE):c.3857G>A (p.Arg1286His)

gnomAD frequency: 0.00005  dbSNP: rs771823596

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000485101	SCV000544017	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 1286 of the POLE protein (p.Arg1286His). This variant is present in population databases (rs771823596, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of attenuated adenomatous polyposis (PMID: 30765821, 31285513, 35957908). ClinVar contains an entry for this variant (Variation ID: 405702). 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	RCV000485101	SCV000569479	uncertain significance	not provided	2024-12-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30765821, 32546565, 31285513, 35957908, 35534704)
Fulgent Genetics, Fulgent Genetics	RCV000765061	SCV000896258	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000485101	SCV001134715	uncertain significance	not provided	2019-03-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000485101	SCV002048414	uncertain significance	not provided	2021-06-22	criteria provided, single submitter	clinical testing	The POLE c.3857G>A; p.Arg1286His variant (rs771823596) is reported in the literature in an individual with attenuated adenomatous polyposis, but was not determined to be causative (Lorca 2019). ARUP Laboratories has detected this variant in an individual with an alternative molecular basis for disease. The variant is listed in the ClinVar database (Variation ID: 405702) and is found in the general population with an overall allele frequency of 0.005% (14/272,190 alleles). The arginine at codon 1286 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL 0.481). 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, given the lack of clinical and functional data, the significance of the p.Arg1286His variant is uncertain at this time. References: 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. PMID: 30523343. Lorca V et al. Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing. Sci Rep. 2019 Jul 8;9(1):9814. PMID: 31285513. 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. PMID: 23263490.
Ambry Genetics	RCV000758175	SCV005481521	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-23	criteria provided, single submitter	clinical testing	The p.R1286H variant (also known as c.3857G>A), located in coding exon 31 of the POLE gene, results from a G to A substitution at nucleotide position 3857. The arginine at codon 1286 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in an individual with multiple adenomatous polyps (Lorca V et al. Sci Rep, 2019 Jul;9:9814). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Molecular Oncology Laboratory, Hospital Clínico San Carlos	RCV000458848	SCV000844941	uncertain significance	Colorectal cancer, susceptibility to, 12	2018-06-01	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000758175	SCV000886712	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-13	no assertion criteria provided	clinical testing