Submissions for variant NM_006231.4(POLE):c.4169G>A (p.Arg1390His)

gnomAD frequency: 0.00011  dbSNP: rs200776293

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000487387	SCV000543916	likely benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000487387	SCV000569826	uncertain significance	not provided	2024-10-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal history of ovarian cancer, breast cancer, melanoma, or astrocytoma (PMID: 28873162, 32522261, 32792570, 31970404, 31265121, 37460928); This variant is associated with the following publications: (PMID: 32522261, 35793867, 32792570, 31970404, 28873162, 31265121, 37460928, 33057194, 35982159)
Ambry Genetics	RCV000565871	SCV000671238	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-06	criteria provided, single submitter	clinical testing	The p.R1390H variant (also known as c.4169G>A), located in coding exon 33 of the POLE gene, results from a G to A substitution at nucleotide position 4169. The arginine at codon 1390 is replaced by histidine, an amino acid with highly similar properties. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487387	SCV000888533	uncertain significance	not provided	2018-01-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487387	SCV002063081	uncertain significance	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000565871	SCV002536837	likely benign	Hereditary cancer-predisposing syndrome	2020-12-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268044	SCV002550100	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002268044	SCV004122075	uncertain significance	not specified	2023-10-24	criteria provided, single submitter	clinical testing	Variant summary: POLE c.4169G>A (p.Arg1390His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 250948 control chromosomes, predominantly at a frequency of 0.0002 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4169G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, Hereditary Non-Polyposis Colon Cancer, Anaplastic Astrocytoma, and unspecified cancer, without strong evidence for causality (example, Velazquez_2020, Zhu_2020, Muskens_2020, Mur_2020). These report(s) do 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 publications have been ascertained in the context of this evaluation (PMID: 32792570, 31970404, 32522261, 31265121). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=6; Likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV004772905	SCV005382095	uncertain significance	Pediatric high-grade glioma		criteria provided, single submitter	research
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415649	SCV000493792	uncertain significance	Colorectal cancer, susceptibility to, 12	2016-03-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358582	SCV001554363	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The POLE p.Arg1390His variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs200776293) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Knight Diagnostic, Invitae, GeneDx, and Ambry Genetics), and Clinvitae (3x). The variant was identified in control databases in 34 of 276722 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24028 chromosomes (freq: 0.000083), Other in 4 of 6452 chromosomes (freq: 0.00062), Latino in 7 of 34346 chromosomes (freq: 0.000204), European (Non-Finnish) in 13 of 126410 chromosomes (freq: 0.000103), Ashkenazi Jewish in 7 of 10114 chromosomes (freq: 0.000692), and South Asian in 1 of 30712 chromosomes (freq: 0.000033); it was not observed in the East Asian or Finnish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Arg1390 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004737464	SCV005362119	uncertain significance	POLE-related disorder	2024-05-12	no assertion criteria provided	clinical testing	The POLE c.4169G>A variant is predicted to result in the amino acid substitution p.Arg1390His. This variant has been reported in association with cancer and interpreted as a variant of uncertain significance (example, supppl. Table 1. Velázquez et al 2020. PubMed ID: 32522261). This variant is reported in 0.077% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as a variant of uncertain significance and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/374972/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.