12-132676210-C-G

Variant names:

• chr12-132676210-C-G
• rs4077170
• NM_006231.4:c.910-6G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006231.4(POLE):​c.910-6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,600,780 control chromosomes in the GnomAD database, including 369,890 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32628 hom., cov: 34)
  • Exomes 𝑓: 0.68 (337262 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006661
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: -0.0250
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-132676210-C-G is Benign according to our data. Variant chr12-132676210-C-G is described in ClinVar as Benign. ClinVar VariationId is 380209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006231.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	NM_006231.4	MANE Select	c.910-6G>C		splice_region intron	N/A	NP_006222.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE	ENST00000320574.10	TSL:1 MANE Select	c.910-6G>C		splice_region intron	N/A	ENSP00000322570.5
	POLE	ENST00000535270.5	TSL:1	c.829-6G>C		splice_region intron	N/A	ENSP00000445753.1
	POLE	ENST00000537064.5	TSL:1	n.910-26G>C		intron	N/A	ENSP00000442578.1

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98692 AN: 152056 Hom.: 32585 Cov.: 34

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.660

GnomAD2 exomes AF: 0.623 AC: 155218 AN: 249280 AF XY: 0.629

Gnomad AFR exome AF: 0.635

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.769

Gnomad EAS exome AF: 0.303

Gnomad FIN exome AF: 0.609

Gnomad NFE exome AF: 0.700

Gnomad OTH exome AF: 0.665

GnomAD4 exome AF: 0.678 AC: 981617 AN: 1448606 Hom.: 337262 Cov.: 28 AF XY: 0.676 AC XY: 487560 AN XY: 721476

African (AFR) AF: 0.641 AC: 21230 AN: 33144

American (AMR) AF: 0.523 AC: 23201 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 20079 AN: 26026

East Asian (EAS) AF: 0.307 AC: 12150 AN: 39598

South Asian (SAS) AF: 0.603 AC: 51714 AN: 85762

European-Finnish (FIN) AF: 0.615 AC: 32314 AN: 52552

Middle Eastern (MID) AF: 0.653 AC: 3747 AN: 5738

European-Non Finnish (NFE) AF: 0.705 AC: 776516 AN: 1101478

Other (OTH) AF: 0.678 AC: 40666 AN: 59952

GnomAD4 genome AF: 0.649 AC: 98782 AN: 152174 Hom.: 32628 Cov.: 34 AF XY: 0.641 AC XY: 47685 AN XY: 74388

African (AFR) AF: 0.635 AC: 26371 AN: 41526

American (AMR) AF: 0.587 AC: 8978 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2702 AN: 3470

East Asian (EAS) AF: 0.307 AC: 1592 AN: 5178

South Asian (SAS) AF: 0.601 AC: 2897 AN: 4824

European-Finnish (FIN) AF: 0.601 AC: 6355 AN: 10576

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47608 AN: 67998

Other (OTH) AF: 0.657 AC: 1388 AN: 2112

Alfa AF: 0.674 Hom.: 9083

Bravo AF: 0.646

Asia WGS AF: 0.518 AC: 1805 AN: 3478

EpiCase AF: 0.714

EpiControl AF: 0.713

ClinVar

Significance: Benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

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: Frequency

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 29, 2015

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.

Oct 03, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

not provided Benign:4 Other:1

May 25, 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 POLE c.910-6G>C intronic variant involves the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant along with 5/5 splice site tools predicting the variant to to have an impact on normal splicing. This variant was found in 76218/120852 control chromosomes (24815 homozygotes) at a frequency of 0.6306722 suggesting the variant to be the ancestral allele and a benign polymorphism. Taken together, this variant is classified as Benign.

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 20, 2024

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

Colorectal cancer, susceptibility to, 12 Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:2

Jul 10, 2025

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 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.

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

POLE-related polyposis and colorectal cancer syndrome Benign:1

Jul 13, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.86
DANN	Benign	0.59
PhyloP100		-0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=40/60	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.018
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: rs4077170; hg19: chr12-133252796; COSMIC: COSV57680623; COSMIC: COSV57680623;