chr12-132632393-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006231.4(POLE):c.6252A>G(p.Ser2084Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 1,613,180 control chromosomes in the GnomAD database, including 301,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33668 hom., cov: 33)

Exomes 𝑓: 0.60 ( 268244 hom. )

Consequence

POLE
NM_006231.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -4.33

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 12-132632393-T-C is Benign according to our data. Variant chr12-132632393-T-C is described in ClinVar as [Benign]. Clinvar id is 380217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132632393-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-4.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.6252A>G	p.Ser2084Ser	synonymous_variant	Exon 45 of 49	ENST00000320574.10	NP_006222.2	Q07864
POLE	XM_011534795.4 link	c.6252A>G	p.Ser2084Ser	synonymous_variant	Exon 45 of 48		XP_011533097.1
POLE	XM_011534797.4 link	c.5331A>G	p.Ser1777Ser	synonymous_variant	Exon 37 of 40		XP_011533099.1
POLE	XM_011534802.4 link	c.3240A>G	p.Ser1080Ser	synonymous_variant	Exon 21 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.6252A>G	p.Ser2084Ser	synonymous_variant	Exon 45 of 49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.659

AC:

100172

AN:

151994

Hom.:

33636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.767

Gnomad AMI

AF:

0.591

Gnomad AMR

AF:

0.736

Gnomad ASJ

AF:

0.526

Gnomad EAS

AF:

0.803

Gnomad SAS

AF:

0.626

Gnomad FIN

AF:

0.579

Gnomad MID

AF:

0.630

Gnomad NFE

AF:

0.588

Gnomad OTH

AF:

0.639

GnomAD3 exomes

AF:

0.644

AC:

161809

AN:

251400

Hom.:

53311

AF XY:

0.632

AC XY:

85904

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.767

Gnomad AMR exome

AF:

0.794

Gnomad ASJ exome

AF:

0.531

Gnomad EAS exome

AF:

0.813

Gnomad SAS exome

AF:

0.613

Gnomad FIN exome

AF:

0.577

Gnomad NFE exome

AF:

0.585

Gnomad OTH exome

AF:

0.627

GnomAD4 exome

AF:

0.603

AC:

881194

AN:

1461068

Hom.:

268244

Cov.:

AF XY:

0.602

AC XY:

437719

AN XY:

726904

show subpopulations

Gnomad4 AFR exome

AF:

0.766

Gnomad4 AMR exome

AF:

0.784

Gnomad4 ASJ exome

AF:

0.532

Gnomad4 EAS exome

AF:

0.806

Gnomad4 SAS exome

AF:

0.610

Gnomad4 FIN exome

AF:

0.574

Gnomad4 NFE exome

AF:

0.586

Gnomad4 OTH exome

AF:

0.612

GnomAD4 genome

AF:

0.659

AC:

100256

AN:

152112

Hom.:

33668

Cov.:

AF XY:

0.660

AC XY:

49103

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.767

Gnomad4 AMR

AF:

0.737

Gnomad4 ASJ

AF:

0.526

Gnomad4 EAS

AF:

0.803

Gnomad4 SAS

AF:

0.626

Gnomad4 FIN

AF:

0.579

Gnomad4 NFE

AF:

0.588

Gnomad4 OTH

AF:

0.641

Alfa

AF:

0.603

Hom.:

48177

Bravo

AF:

0.675

Asia WGS

AF:

0.698

AC:

2425

AN:

3478

EpiCase

AF:

0.575

EpiControl

AF:

0.575

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Oct 17, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Oct 30, 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. -

not provided

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 17, 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 c.6252G>A (p.Ser2084=) in POLE gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.638 (77431/1211338 chrs tested) including numerous homozygous occurrences. The variant of interest has not, to our knowledge, been reported in affected individuals or cited by reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

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

- -

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

- -

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

- -

Hereditary cancer-predisposing syndrome

Benign:1

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. -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.41

DANN

Benign

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over