chr12-132660983-C-T

Variant names:

• chr12-132660983-C-T
• rs147692158
• NM_006231.4:c.3046G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 7.77
• Publications: 6 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 -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 CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 220916. Variant chr12-132660983-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 220916. Variant chr12-132660983-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 220916. Variant chr12-132660983-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id 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
POLE	NM_006231.4	c.3046G>A	p.Val1016Met	missense_variant	Exon 25 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3046G>A	p.Val1016Met	missense_variant	Exon 25 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152122 Hom.: 0 Cov.: 32

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

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

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

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74440

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

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:5 Benign:8

Revision: criteria provided, conflicting classifications

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:2 Benign: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:1 Benign: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

Other links and lift over

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