Submissions for variant NM_006231.4(POLE):c.16G>C (p.Gly6Arg)

gnomAD frequency: 0.00293  dbSNP: rs202220778

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202795	SCV000258038	likely benign	not specified	2015-07-22	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000210904	SCV000264609	likely benign	Colorectal cancer	2015-11-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000432993	SCV000289265	benign	not provided	2025-02-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000233156	SCV000488841	likely benign	Colorectal cancer, susceptibility to, 12	2016-07-06	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000432993	SCV000511481	uncertain significance	not provided	2016-11-10	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000202795	SCV000518043	likely benign	not specified	2017-12-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000568177	SCV000671367	benign	Hereditary cancer-predisposing syndrome	2019-11-06	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202795	SCV000698662	benign	not specified	2019-08-05	criteria provided, single submitter	clinical testing	Variant summary: POLE c.16G>C (p.Gly6Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 110214 control chromosomes, predominantly at a frequency of 0.0045 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 317 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.16G>C has been reported in the literature in individuals affected with Colorectal Cancer (ex Kothari_2016). 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. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Nine of these ten have classified the variant as benign (n=3)/likely benign (n=6). Based on the evidence outlined above, the variant was re-evaluated as benign.
PreventionGenetics, part of Exact Sciences	RCV000432993	SCV000806726	likely benign	not provided	2017-02-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202795	SCV000889712	benign	not specified	2018-04-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000432993	SCV001148917	likely benign	not provided	2025-03-01	criteria provided, single submitter	clinical testing	POLE: BS2
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000432993	SCV002009605	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000202795	SCV002071627	likely benign	not specified	2021-10-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000568177	SCV002536763	benign	Hereditary cancer-predisposing syndrome	2020-07-31	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202795	SCV002550233	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000233156	SCV002761454	likely benign	Colorectal cancer, susceptibility to, 12	2019-12-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000432993	SCV004562143	likely benign	not provided	2024-11-04	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000568177	SCV000788161	likely benign	Hereditary cancer-predisposing syndrome	2017-12-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355562	SCV001550484	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Gly6Arg variant was not identified in the literature nor was it identified in the MutDB database. The variant was identified in the following databases: dbSNP (ID: rs202220778) as “With other allele”, ClinVar and Clinvitae (9x as benign by Invitae and Ambry Genetics, as likely benign by Children's Hospital of Philadelphia, University of Washington Medical Center, Counsyl, GeneDx, Quest Diagnostics, Integrated Genetics, and as uncertain significance by Center for Pediatric Genomic Medicine). The variant was identified in control databases in 353 of 136976 chromosomes (2 homozygous) at a frequency of 0.0025 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African in 13 of 11652 chromosomes (freq: 0.0011), “Other” in 11 of 3924 chromosomes (freq: 0.003), Latino in 51 of 21270 chromosomes (freq: 0.002), European Non-Finnish in 220 of 52786 chromosomes (freq: 0.004), Ashkenazi Jewish in 44 of 7670 chromosomes (freq: 0.006), European Finnish in 10 of 11688 chromosomes (freq: 0.00085), and South Asian in 4 of 19714 chromosomes (freq: 0.000203). While the variant was not observed in the East Asian, populations. The p.Gly6Arg residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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 this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000432993	SCV001799699	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000432993	SCV001807904	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000432993	SCV001917162	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000432993	SCV001971563	likely benign	not provided		no assertion criteria provided	clinical testing