rs5744886

Variant names:

• chr12-132657434-A-G
• rs5744886
• NM_006231.4:c.3379-5T>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.3379-5T>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 0.0267 in 1,613,706 control chromosomes in the GnomAD database, including 1,214 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 0.026 (146 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1068 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004335
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.264
• Publications: 3 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=-0.8).
• BP6: Variant 12-132657434-A-G is Benign according to our data. Variant chr12-132657434-A-G is described in ClinVar as Benign. ClinVar VariationId is 380222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.3379-5T>C		splice_region_variant, intron_variant	Intron 27 of 48	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3379-5T>C		splice_region_variant, intron_variant	Intron 27 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 4009 AN: 152146 Hom.: 139 Cov.: 32

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0382 AC: 9593 AN: 250962 AF XY: 0.0331

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.00686

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0243

Gnomad OTH exome AF: 0.0323

GnomAD4 exome AF: 0.0267 AC: 38990 AN: 1461442 Hom.: 1068 Cov.: 35 AF XY: 0.0256 AC XY: 18601 AN XY: 726998

African (AFR) AF: 0.00421 AC: 141 AN: 33470

American (AMR) AF: 0.156 AC: 6987 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00685 AC: 179 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.00730 AC: 629 AN: 86210

European-Finnish (FIN) AF: 0.0312 AC: 1669 AN: 53410

Middle Eastern (MID) AF: 0.00315 AC: 18 AN: 5706

European-Non Finnish (NFE) AF: 0.0252 AC: 28002 AN: 1111744

Other (OTH) AF: 0.0225 AC: 1361 AN: 60374

GnomAD4 genome AF: 0.0264 AC: 4025 AN: 152264 Hom.: 146 Cov.: 32 AF XY: 0.0283 AC XY: 2104 AN XY: 74454

African (AFR) AF: 0.00590 AC: 245 AN: 41558

American (AMR) AF: 0.109 AC: 1661 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00830 AC: 40 AN: 4822

European-Finnish (FIN) AF: 0.0313 AC: 332 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0241 AC: 1639 AN: 68008

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0224 Hom.: 27

Bravo AF: 0.0301

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0202

EpiControl AF: 0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Nov 06, 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. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 02, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLE c.3379-5T>C variant was not identified in the literature, Cosmic, MutDB, or LOVD 3.0. The variant was identified in dbSNP (ID: rs5744886) as “With Benign allele” and ClinVar (classified benign by GeneDx, Laboratory for Molecular Medicine/Partners HealthCare Personalized Medicine, Invitae, and Ambry Genetics). The variant was also identified in control databases in 10094 (549 homozygous) of 276806 chromosomes at a frequency of 0.04 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 5548 (480 homozygous) of 34370 chromosomes (freq: 0.2), African in 136 of 24016 chromosomes (freq: 0.006), Other in 229 (8 homozygous) of 6464 chromosomes (freq: 0.04), European in 3101 (46 homozygous) of 126470 chromosomes (freq: 0.02), Ashkenazi Jewish in 71 (1 homozygous) of 10144 chromosomes (freq: 0.007), East Asian in 4 of 18868 chromosomes (freq: 0.0002), Finnish in 790 (13 homozygous) of 25700 chromosomes (freq: 0.03), and South Asian in 215 (1 homozygous) of 30774 chromosomes (freq: 0.007). The c.3379-5T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. Positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; however, 5 of 5 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. -

not provided Benign:4

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 19, 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: c.3379-5T>C in POLE gene is an intronic change that involves a non-conserved nucleotide. The variant is present in the control population dataset of ExAC at frequency of 0.0333 (3963/118996 chrs tested), predominantly in individuals of Latin descent (0.17; 1945/11380 chrs tested) including numerous homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0014%, suggesting that it is a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports or cited by reputable databases/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Benign:3

Jan 15, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The splice region variant NM_006231.4(POLE):c.3379-5T>C has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380222 as of 2025-01-02). The variant is observed in one or more well-documented healthy adults.The c.3379-5T>C variant is observed in 135/5,008 (2.6957%) alleles from individuals of 1kG All background in 1kG, indicating it is a common benign variant. The c.3379-5T>C variant is not predicted to disrupt the existing acceptor splice site 3bp upstream by any splice site algorithm. The c.3379-5T>C variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign. -

May 20, 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. -

Dec 08, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 12 Benign:1

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
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.49
PhyloP100		0.26
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.036
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: rs5744886; hg19: chr12-133234020;