NM_006231.4:c.16G>C

Variant names:

• chr12-132687300-C-G
• rs202220778
• NM_006231.4:c.16G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006231.4(POLE):​c.16G>C​(p.Gly6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,505,724 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (27 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:21
• Conservation: PhyloP100: -0.427
• Publications: 7 publications found

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

POLE Gene-Disease associations (from GenCC):

• POLE-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 12

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

  Inheritance: AR Classification: STRONG Submitted by: G2P
• IMAGe syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046218634).
• BP6: Variant 12-132687300-C-G is Benign according to our data. Variant chr12-132687300-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218680.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00288 (438/152078) while in subpopulation NFE AF = 0.00499 (339/67942). AF 95% confidence interval is 0.00455. There are 0 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 27 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.16G>C	p.Gly6Arg	missense_variant	Exon 1 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.16G>C	p.Gly6Arg	missense_variant	Exon 1 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 151968 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000474

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00499

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00266 AC: 293 AN: 110214 AF XY: 0.00260

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00584

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000829

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00242

GnomAD4 exome AF: 0.00510 AC: 6903 AN: 1353646 Hom.: 27 Cov.: 32 AF XY: 0.00505 AC XY: 3376 AN XY: 667944

African (AFR) AF: 0.000348 AC: 10 AN: 28764

American (AMR) AF: 0.00265 AC: 87 AN: 32890

Ashkenazi Jewish (ASJ) AF: 0.00453 AC: 110 AN: 24304

East Asian (EAS) AF: 0.0000309 AC: 1 AN: 32414

South Asian (SAS) AF: 0.000502 AC: 38 AN: 75762

European-Finnish (FIN) AF: 0.000801 AC: 31 AN: 38696

Middle Eastern (MID) AF: 0.00189 AC: 9 AN: 4762

European-Non Finnish (NFE) AF: 0.00596 AC: 6319 AN: 1060006

Other (OTH) AF: 0.00532 AC: 298 AN: 56048

GnomAD4 genome AF: 0.00288 AC: 438 AN: 152078 Hom.: 0 Cov.: 33 AF XY: 0.00262 AC XY: 195 AN XY: 74366

African (AFR) AF: 0.00106 AC: 44 AN: 41538

American (AMR) AF: 0.00131 AC: 20 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.000474 AC: 5 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00499 AC: 339 AN: 67942

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00266 Hom.: 0

Bravo AF: 0.00316

ESP6500AA AF: 0.000842 AC: 2

ESP6500EA AF: 0.00197 AC: 10

ExAC AF: 0.00138 AC: 42

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:21

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:8

Feb 20, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLE: BS2 -

not specified Benign:6

Apr 17, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Dec 07, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Hereditary cancer-predisposing syndrome Benign:3

Jul 31, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 01, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 06, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Colorectal cancer, susceptibility to, 12 Benign:2

Jul 06, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 31, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: 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. -

Colorectal cancer Benign:1

Nov 01, 2015

CSER _CC_NCGL, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Benign	0.044	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N;.
PhyloP100		-0.43
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.10	N;N
REVEL	Benign	0.032
Sift	Benign	0.22	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.0	B;B
Vest4		0.063
MVP		0.25
MPC		0.24
ClinPred		0.026	T
GERP RS		2.5
PromoterAI		-0.012	Neutral
Varity_R		0.025
gMVP		0.28
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202220778; hg19: chr12-133263886; COSMIC: COSV57686759; COSMIC: COSV57686759;