Submissions for variant NM_006231.4(POLE):c.6674G>A (p.Arg2225His)

gnomAD frequency: 0.00012  dbSNP: rs538875477

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000479804	SCV000289476	uncertain significance	not provided	2024-02-01	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 2225 of the POLE protein (p.Arg2225His). This variant is present in population databases (rs538875477, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 240612). 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.
GeneDx	RCV000479804	SCV000569131	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in patients with breast cancer in published literature (PMID: 35264596, 38136308, 35534704); This variant is associated with the following publications: (PMID: 29056344, 19296856, 35534704, 35264596, 38136308)
Fulgent Genetics, Fulgent Genetics	RCV000763806	SCV000894723	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV003492011	SCV001138851	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000229333	SCV002584688	uncertain significance	Colorectal cancer, susceptibility to, 12	2022-10-03	criteria provided, single submitter	clinical testing	The POLE c.6674G>A (p.Arg2225His) missense change has a maximum subpopulation frequency of 0.014% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics	RCV002365206	SCV002663970	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-04	criteria provided, single submitter	clinical testing	The c.6674G>A (p.R2225H) alteration is located in exon 48 (coding exon 48) of the POLE gene. This alteration results from a G to A substitution at nucleotide position 6674, causing the arginine (R) at amino acid position 2225 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596142	SCV005090420	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357188	SCV001552572	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Arg2225His variant was not identified in the literature nor was it identified in the Cosmic, or MutDB databases. The variant was identified in dbSNP (ID: rs538875477) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, GeneDx). The variant was identified in control databases in 19 of 276514 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23978 chromosomes (freq: 0.0001), Latino in 5 of 34404 chromosomes (freq: 0.0002), European in 11 of 126158 chromosomes (freq: 0.0001), and Finnish in 1 of 25742 chromosome (freq: 0.00004); it was not observed in the Other, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Arg2225 residue is conserved in in mammals but not in more distantly related organisms and 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. 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. 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	RCV004532935	SCV004752392	uncertain significance	POLE-related disorder	2023-12-29	no assertion criteria provided	clinical testing	The POLE c.6674G>A variant is predicted to result in the amino acid substitution p.Arg2225His. This variant has been reported in a mutagenesis screen (Table S2, Campbell et al. 2017. PubMed ID: 29056344). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/240612/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.