Submissions for variant NM_006231.4(POLE):c.1337G>A (p.Arg446Gln)

gnomAD frequency: 0.00046  dbSNP: rs151273553

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000657099	SCV000262196	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000657099	SCV000322490	likely benign	not provided	2021-05-30	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 adenomatous polyposis, endometrial cancer, or malignant melanoma (Church 2013, Spier 2014, Aoude 2015); This variant is associated with the following publications: (PMID: 25583476, 25986922, 26251183, 25529843, 23528559, 24844595, 28188185, 29056344, 22960745, 31320401, 31034466)
Counsyl	RCV000205876	SCV000488770	uncertain significance	Colorectal cancer, susceptibility to, 12	2016-08-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569920	SCV000671276	likely benign	Hereditary cancer-predisposing syndrome	2021-08-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003389710	SCV000806715	uncertain significance	POLE-related condition	2023-05-08	criteria provided, single submitter	clinical testing	The POLE c.1337G>A variant is predicted to result in the amino acid substitution p.Arg446Gln. This variant has been reported in individuals with metastatic colorectal cancer (Gong et al. 2017. PubMed ID: 28188185), colorectal adenomatous polyposis (Spier et al. 2015. PubMed ID: 25529843), endometrial cancer (Church et al. 2013. PubMed ID: 23528559; Meng et al. 2014. PubMed 24844595), cutaneous malignant melanoma (Aoude et al. 2015. PubMed ID: 26251183), and gastric cancer (Table S3, Chen et al. 2015. PubMed ID: 25583476). This variant has also been reported as a passenger variant and was considered a false positive finding during a genetic screening of individuals with cancer (Campbell et al. 2017. PubMed ID: 29056344). This variant is reported in 0.053% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133250183-C-T) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/221066/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mendelics	RCV000709276	SCV000838707	uncertain significance	Familial colorectal cancer	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657099	SCV000888493	likely benign	not provided	2023-05-22	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000205876	SCV001761621	uncertain significance	Colorectal cancer, susceptibility to, 12	2021-06-24	criteria provided, single submitter	clinical testing	The POLE c.1337G>A; p.Arg446Gln missense change has a maximum subpopulation frequency of 0.053% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-133250183-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. Structural analysis indicates that the affected residue is distance from both the exonuclease and polymerase active sites (PMID: 23528559). This variant has been reported in an individual with endometrial cancer (PMID: 23528559), cutaneous malignant melanoma (PMID: 26251183), and polyposis with >100 polyps at age 28 (PMID: 25529843). It has been observed in tumors that did not exhibit a hypermutator phenotype (PMID: 29056344). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no criteria met.
Sema4, Sema4	RCV000569920	SCV002536746	likely benign	Hereditary cancer-predisposing syndrome	2021-07-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000255280	SCV002550188	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000205876	SCV004018513	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-04-19	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000657099	SCV001548809	uncertain significance	not provided		no assertion criteria provided	clinical testing	The POLE p.R446Q variant was reported in the literature in individuals with colorectal cancer, colorectal adenomatous polyposis, endometrial cancer, or cutaneous malignant melanoma (Church_2013_PMID:23528559; Spier_2015_PMID:25529843; Aoude_2015_ PMID:26251183; Choi_2019_PMID:31320401). The variant was identified in dbSNP (ID: rs151273553), ClinVar (classified as uncertain significance by Counsyl, Quest Diagnostics, PreventionGenetics, Mendelics, Ambry Genetics, and GeneDx, and as likely benign by Invitae) and Cosmic. The variant was identified in control databases in 72 of 267402 chromosomes at a frequency of 0.0002693 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: European (non-Finnish) in 63 of 118046 chromosomes (freq: 0.000534), African in 4 of 23594 chromosomes (freq: 0.00017), European (Finnish) in 3 of 24348 chromosomes (freq: 0.000123) and Latino in 2 of 35088 chromosomes (freq: 0.000057), but was not observed in the Ashkenazi Jewish, East Asian, Other, or South Asian populations. The p.R446 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Structural analysis reveals that this variant is distant from both exonuclease and polymerase active sites (Church_2013_PMID:23528559). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
Genetic Services Laboratory, University of Chicago	RCV000255280	SCV003839901	uncertain significance	not specified	2022-11-07	no assertion criteria provided	clinical testing	DNA sequence analysis of the POLE gene demonstrated a sequence change, c.1337G>A, in exon 13 that results in an amino acid change, p.Arg446Gln. This sequence change has been previously described in one individual with sporadic classical polyposis (PMID: 25529843). This sequence change has been described in the gnomAD database with a frequency of 0.028% in the overall subpopulation (dbSNP rs151273553). The p.Arg446Gln change affects a highly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg446Gln substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg446Gln change remains unknown at this time.