rs5744936

Variant names:

• chr12-132643832-G-A
• rs5744936
• NM_006231.4:c.4290+5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006231.4(POLE):​c.4290+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,612,088 control chromosomes in the GnomAD database, including 528 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 0.021 (53 hom., cov: 33)
  • Exomes 𝑓: 0.023 (475 hom.)
• Consequence: POLE NM_006231.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001190
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.0120
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-132643832-G-A is Benign according to our data. Variant chr12-132643832-G-A is described in ClinVar as Benign. ClinVar VariationId is 380226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0207 (3155/152292) while in subpopulation EAS AF = 0.028 (145/5186). AF 95% confidence interval is 0.0265. There are 53 homozygotes in GnomAd4. There are 1600 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.4290+5C>T		splice_region_variant, intron_variant	Intron 33 of 48	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.4290+5C>T		splice_region_variant, intron_variant	Intron 33 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 3157 AN: 152174 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0236 AC: 5910 AN: 250510 AF XY: 0.0241

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.0340

Gnomad FIN exome AF: 0.0417

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0233 AC: 34014 AN: 1459796 Hom.: 475 Cov.: 32 AF XY: 0.0236 AC XY: 17126 AN XY: 725830

African (AFR) AF: 0.00356 AC: 119 AN: 33446

American (AMR) AF: 0.0124 AC: 555 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 443 AN: 26100

East Asian (EAS) AF: 0.0290 AC: 1151 AN: 39632

South Asian (SAS) AF: 0.0214 AC: 1843 AN: 86172

European-Finnish (FIN) AF: 0.0418 AC: 2230 AN: 53406

Middle Eastern (MID) AF: 0.0105 AC: 60 AN: 5740

European-Non Finnish (NFE) AF: 0.0237 AC: 26335 AN: 1110332

Other (OTH) AF: 0.0212 AC: 1278 AN: 60320

GnomAD4 genome AF: 0.0207 AC: 3155 AN: 152292 Hom.: 53 Cov.: 33 AF XY: 0.0215 AC XY: 1600 AN XY: 74464

African (AFR) AF: 0.00423 AC: 176 AN: 41570

American (AMR) AF: 0.0189 AC: 289 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3472

East Asian (EAS) AF: 0.0280 AC: 145 AN: 5186

South Asian (SAS) AF: 0.0255 AC: 123 AN: 4824

European-Finnish (FIN) AF: 0.0414 AC: 439 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0275 AC: 1872 AN: 68008

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.0244 Hom.: 122

Bravo AF: 0.0172

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.0231

EpiControl AF: 0.0226

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Oct 28, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

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

- -

-

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

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

- -

Dec 01, 2016

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

not provided Benign:5

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: The POLE c.4290+5C>T variant involves the alteration of a non-conserved nucleotide located in an intronic position outside of the canonical slice sites. Mutation taster predicts a damaging outcome for this variant while 5/5 in silico tools via Alamut predict the variant no to have a significant impact on splicing. The variant was found in 2827/117634 control chromosomes (40 homozygotes) at a frequency of 0.0240322, which is approximately 1692 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Benign. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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:4

Jan 20, 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.4290+5C>T has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380226 as of 2025-01-02). The c.4290+5C>T variant is observed in 108/5,008 (2.1565%) alleles from individuals of 1kG All background in 1kG, indicating it is a common benign variant. The c.4290+5C>T variant is not predicted to disrupt the existing donor splice site 3bp upstream by any splice site algorithm. The c.4290+5C>T variant is predicted to introduce a novel splice site by 1 of 4 splice site algorithms. The c.4290+5C>T 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 -

Feb 28, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 21, 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 24, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

- -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLE c.4290+5C>T variant was not identified in the literature nor was it identified in the Cosmic and MutDB databases. The variant was identified in dbSNP (ID: rs5744936) “With Benign allele”, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (2x), and in control databases in 6696 (102 homozygous) of 276312 chromosomes at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 94 (1 homozygous) of 24002 chromosomes (freq: 0.004), Other in 171 (1 homozygous) of 6448 chromosomes (freq: 0.03), Latino in 414 (2 homozygous) of 34364 chromosomes (freq: 0.01), European Non-Finnish in 3397 (47 homozygous) of 126076 chromosomes (freq: 0.03), Ashkenazi Jewish in 162 (1 homozygous) of 10110 chromosomes (freq: 0.02), East Asian in 626 (12 homozygous) of 18858 chromosomes (freq: 0.03), European Finnish in 1086 (27 homozygous) of 25750 chromosomes (freq: 0.04), and South Asian in 746 (11 homozygous) of 30704 chromosomes (freq: 0.02). The c.4290+5C>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.40
PhyloP100		-0.012
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0040
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: rs5744936; hg19: chr12-133220418;