12-132626230-C-T

Variant names:

• chr12-132626230-C-T
• rs5745066
• NM_006231.4:c.6418G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006231.4(POLE):​c.6418G>A​(p.Glu2140Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0187 in 1,613,774 control chromosomes in the GnomAD database, including 387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (25 hom., cov: 33)
  • Exomes 𝑓: 0.019 (362 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 4.03

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039714277).
• BP6: Variant 12-132626230-C-T is Benign according to our data. Variant chr12-132626230-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132626230-C-T is described in Lovd as [Benign]. Variant chr12-132626230-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0136 (2069/152264) while in subpopulation NFE AF= 0.0214 (1456/68012). AF 95% confidence interval is 0.0205. There are 25 homozygotes in gnomad4. There are 955 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.6418G>A	p.Glu2140Lys	missense_variant	Exon 46 of 49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6418G>A	p.Glu2140Lys	missense_variant	Exon 46 of 48		XP_011533097.1
POLE	XM_011534797.4	c.5497G>A	p.Glu1833Lys	missense_variant	Exon 38 of 40		XP_011533099.1
POLE	XM_011534802.4	c.3406G>A	p.Glu1136Lys	missense_variant	Exon 22 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6418G>A	p.Glu2140Lys	missense_variant	Exon 46 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2070 AN: 152146 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.00815

GnomAD3 exomes AF: 0.0147 AC: 3687 AN: 251010 Hom.: 52 AF XY: 0.0144 AC XY: 1951 AN XY: 135780

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00216

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0192 AC: 28112 AN: 1461510 Hom.: 362 Cov.: 32 AF XY: 0.0188 AC XY: 13694 AN XY: 727064

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.00449

Gnomad4 ASJ exome AF: 0.00586

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.0286

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0136 AC: 2069 AN: 152264 Hom.: 25 Cov.: 33 AF XY: 0.0128 AC XY: 955 AN XY: 74450

Gnomad4 AFR AF: 0.00392

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0292

Gnomad4 NFE AF: 0.0214

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.0188 Hom.: 62

Bravo AF: 0.0121

TwinsUK AF: 0.0240 AC: 89

ALSPAC AF: 0.0272 AC: 105

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0210 AC: 181

ExAC AF: 0.0157 AC: 1906

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0195

EpiControl AF: 0.0199

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 22, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

GeneDx

Significance: 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. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLE p.Glu2140Lys variant was identified to be associated with an increased risk of breast cancer in a study looking at the potential that markers in DNA repair pathways collectively show an association with breast cancer when any single marker is too weak to find an association (Monsees_2011). The variant was also identified in dbSNP (ID: rs5745066) “With other allele”, ClinVar (classified benign by Invitae, GeneDx, Ambry Genetics, and Laboratory Corporation of America, and likely benign by Counsyl and Quest Diagnostics Institute San Juan Capistrano) and Clinvitae (3x), and was not identified in Cosmic and MutDB. The variant was identified in control databases in 4149 of 276872 chromosomes (56 homozygous) at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 78 of 23996 chromosomes (freq: 0.003), Other in 102 (1 homozygous)of 6462 chromosomes (freq: 0.02), Latino in 124 (2 homozygous) of 34408 chromosomes (freq: 0.004), European Non-Finnish in 2973 (38 homozygous)of 126440 chromosomes (freq: 0.02), Ashkenazi Jewish in 59 (1 homozygous)of 10142 chromosomes (freq: 0.006), European Finnish in 749 (12 homozygous) of 25788 chromosomes (freq: 0.03), and South Asian in 64 (2 homozygous) of 30774 chromosomes (freq: 0.002); it was not observed in the East Asian population. The p.Glu2140 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 of the variant Lys 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 this variant meets our laboratory's criteria to be classified as benign. -

Sep 04, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:6

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLE: BS1, BS2 -

Aug 17, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.6418G>A (p.Glu2140Lysl) in POLE gene is a missense change that involves a conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at an overall frequency 0.0159 (1899/119208 chrs tested) predominantly in individuals of European ancestry (0.025; 1784/72012 chrs tested). The latter frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.000014). The variant has not, to our knowledge, been reported in affected individuals, but is cited as Benign by a reputable database/clinical laboratory. Taking together, the variant was classified as Benign. -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

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

- -

Hereditary cancer-predisposing syndrome Benign:3

May 11, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 19, 2015

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. -

Feb 15, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 12 Benign:2

Jun 07, 2016

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.027
Sift	Benign	0.087	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.29	B;.
Vest4		0.33
MPC		0.25
ClinPred		0.016	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.15
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs5745066; hg19: chr12-133202816; COSMIC: COSV57676946; COSMIC: COSV57676946;