12-132665430-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006231.4(POLE):c.2340G>A(p.Ser780Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,611,578 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S780S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 51 hom., cov: 31)

Exomes 𝑓: 0.023 ( 480 hom. )

Consequence

POLE
NM_006231.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -3.78

Publications

8 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

POLE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-132665430-C-T is Benign according to our data. Variant chr12-132665430-C-T is described in ClinVar as Benign. ClinVar VariationId is 380225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.78 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0207 (3151/152256) while in subpopulation EAS AF = 0.028 (145/5180). AF 95% confidence interval is 0.0265. There are 51 homozygotes in GnomAd4. There are 1600 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 51 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.2340G>A	p.Ser780Ser	synonymous_variant	Exon 21 of 49	ENST00000320574.10	NP_006222.2	Q07864

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.2340G>A	p.Ser780Ser	synonymous_variant	Exon 21 of 49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.0207

AC:

3153

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00427

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.0279

Gnomad SAS

AF:

0.0263

Gnomad FIN

AF:

0.0411

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0275

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0235

AC:

5866

AN:

249490

AF XY:

0.0241

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.0157

Gnomad EAS exome

AF:

0.0339

Gnomad FIN exome

AF:

0.0421

Gnomad NFE exome

AF:

0.0252

Gnomad OTH exome

AF:

0.0250

GnomAD4 exome

AF:

0.0234

AC:

34091

AN:

1459322

Hom.:

480

Cov.:

AF XY:

0.0237

AC XY:

17200

AN XY:

726062

show subpopulations

African (AFR)

AF:

0.00359

AC:

120

AN:

33470

American (AMR)

AF:

0.0125

AC:

557

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

444

AN:

26134

East Asian (EAS)

AF:

0.0290

AC:

1152

AN:

39698

South Asian (SAS)

AF:

0.0217

AC:

1871

AN:

86258

European-Finnish (FIN)

AF:

0.0419

AC:

2146

AN:

51206

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0238

AC:

26455

AN:

1111714

Other (OTH)

AF:

0.0213

AC:

1283

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1744

3488

5231

6975

8719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

918

1836

2754

3672

4590

<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:

0.0207

AC:

3151

AN:

152256

Hom.:

Cov.:

AF XY:

0.0215

AC XY:

1600

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00426

AC:

177

AN:

41574

American (AMR)

AF:

0.0187

AC:

286

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3468

East Asian (EAS)

AF:

0.0280

AC:

145

AN:

5180

South Asian (SAS)

AF:

0.0259

AC:

125

AN:

4822

European-Finnish (FIN)

AF:

0.0411

AC:

436

AN:

10598

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0275

AC:

1871

AN:

68006

Other (OTH)

AF:

0.0199

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

150

301

451

602

752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0217

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.0380

AC:

132

AN:

3478

EpiCase

AF:

0.0231

EpiControl

AF:

0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Nov 22, 2016

PreventionGenetics, part of Exact Sciences

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

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 28, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 24, 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.2340G>A (p.Ser780Ser) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing, while ESE finder predicts alterations to ESE binding sites. However, these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2835/120810 (40 homozygotes, 1/42, frequency: 0.0234666), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic POLE variant of 1/70422 (0.0000142), suggesting this variant is likely a benign polymorphism. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

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 synonymous variant NM_006231.4(POLE):c.2340G>A (p.Ser780=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380225 as of 2025-01-02). The p.Ser780= variant is observed in 107/5,008 (2.1366%) alleles from individuals of 1kG All background in 1kG, indicating it is a common benign variant. The p.Ser780= variant is not predicted to disrupt an existing splice site. The p.Ser780= 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 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. -

Feb 28, 2018

True Health Diagnostics

Significance:Likely benign

Review Status:no assertion criteria provided

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 p.Ser780= variant was not identified in the literature nor was it identified in the Cosmic and MutDB. The variant was identified in dbSNP (ID: rs5744822) â€šÃ„ÃºWith Benign ,Likely benign alleleâ€šÃ„Ã¹, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x) and in control databases in 6661 (103 homozygous) of 275298 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 95 (1 homozygous) of 24026 chromosomes (freq: 0.004), Other in 168 (1 homozygous) of 6440 chromosomes (freq: 0.03), Latino in 414 (2 homozygous) of 34414 chromosomes (freq: 0.01), European Non-Finnish in 3414 (47 homozygous) of 126558 chromosomes (freq: 0.03), Ashkenazi Jewish in 163 (1 homozygous) of 10146 chromosomes (freq: 0.02), East Asian in 624 (12 homozygous) of 18856 chromosomes (freq: 0.03), European Finnish in 1026 (27 homozygous) of 24078 chromosomes (freq: 0.04), and South Asian in 757 (12 homozygous) of 30780 chromosomes (freq: 0.02). The p.Ser780= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

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

0.031

(source)

DANN

Benign

0.56

PhyloP100

-3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over