chr12-132660983-C-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_006231.4(POLE):​c.3046G>A​(p.Val1016Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,611,244 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1016V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

4
5
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:8

Conservation

PhyloP100: 7.77

Publications

6 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10815844).
BP6
Variant 12-132660983-C-T is Benign according to our data. Variant chr12-132660983-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220916.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000644 (98/152240) while in subpopulation NFE AF = 0.00113 (77/67998). AF 95% confidence interval is 0.000928. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLENM_006231.4 linkc.3046G>A p.Val1016Met missense_variant Exon 25 of 49 ENST00000320574.10 NP_006222.2 Q07864

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkc.3046G>A p.Val1016Met missense_variant Exon 25 of 49 1 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
AF:
0.000644
AC:
98
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000471
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00113
Gnomad OTH
AF:
0.000958
GnomAD2 exomes
AF:
0.000777
AC:
193
AN:
248236
AF XY:
0.000775
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.000204
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000375
Gnomad NFE exome
AF:
0.00153
Gnomad OTH exome
AF:
0.000990
GnomAD4 exome
AF:
0.00105
AC:
1538
AN:
1459004
Hom.:
1
Cov.:
31
AF XY:
0.000988
AC XY:
717
AN XY:
725734
show subpopulations
African (AFR)
AF:
0.000150
AC:
5
AN:
33418
American (AMR)
AF:
0.000203
AC:
9
AN:
44410
Ashkenazi Jewish (ASJ)
AF:
0.0000386
AC:
1
AN:
25882
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39674
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85878
European-Finnish (FIN)
AF:
0.000658
AC:
35
AN:
53152
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5742
European-Non Finnish (NFE)
AF:
0.00127
AC:
1412
AN:
1110562
Other (OTH)
AF:
0.00124
AC:
75
AN:
60286
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
73
146
219
292
365
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
58
116
174
232
290
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000644
AC:
98
AN:
152240
Hom.:
0
Cov.:
32
AF XY:
0.000551
AC XY:
41
AN XY:
74440
show subpopulations
African (AFR)
AF:
0.000289
AC:
12
AN:
41552
American (AMR)
AF:
0.000131
AC:
2
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.000471
AC:
5
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00113
AC:
77
AN:
67998
Other (OTH)
AF:
0.000948
AC:
2
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
4
8
13
17
21
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000971
Hom.:
0
Bravo
AF:
0.000589
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00116
AC:
10
ExAC
AF:
0.000972
AC:
118
EpiCase
AF:
0.00120
EpiControl
AF:
0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:8
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:4
Feb 26, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 29, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28873162, 21701589, 29458332) -

Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

POLE: BS1 -

not specified Uncertain:2Benign:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 31, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in affected individuals. It is classified in ClinVar with 1 star as Likely benign by Invitae and VUS by GeneDx. It is present in ExAC at a MaxMAF of 0.15% (high for disease incidence and gene contribution). -

May 14, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: POLE c.3046G>A (p.Val1016Met) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain (IPR006134) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 248236 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 55 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 benign. c.3046G>A has been reported in the literature in individuals affected with various tumor phenotypes, e.g. colorectal cancer and cutaneous melanoma, but without strong evidence of causality (Dominguez-Valentin_2018, Pritchard_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one classified as likely benign while the others classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Feb 27, 2024
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. -

Sep 07, 2018
True Health Diagnostics
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jul 15, 2021
Sema4, Sema4
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Colorectal cancer, susceptibility to, 12 Uncertain:1
May 28, 2019
Mendelics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Malignant tumor of breast Uncertain:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The POLE p.Val1016Met variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs147692158) as “With Uncertain significance allele” and ClinVar (as likely benign by Invitae, and uncertain significance by GeneDx, Laboratory for Molecular Medicine Partners Health Care Personalized Medicine, Quest Diagnostics and Ambry Genetics). The variant was identified in control databases in 206 of 273880 chromosomes (1 homozygous) at a frequency of 0.0008 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 5 of 24010 chromosomes (freq: 0.0002), Other in 6 of 6400 chromosomes (freq: 0.0009), Latino in 8 of 34170 chromosomes (freq: 0.0002), European (Non-Finnish) in 172 of 124734 chromosomes (freq: 0.001), Finnish in 15 of 25468 chromosomes (freq: 0.0006); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Val1016 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. 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. -

POLE-related disorder Benign:1
May 01, 2023
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T;.
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.0090
T
MetaRNN
Benign
0.11
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L;.
PhyloP100
7.8
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-2.4
N;N
REVEL
Benign
0.18
Sift
Benign
0.057
T;T
Sift4G
Uncertain
0.051
T;T
Polyphen
0.48
P;P
Vest4
0.78
MVP
0.31
MPC
1.6
ClinPred
0.10
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.23
gMVP
0.51
Mutation Taster
=78/22
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

Publications

Other links and lift over

dbSNP: rs147692158; hg19: chr12-133237569; COSMIC: COSV99075394; COSMIC: COSV99075394; API