12-132677696-A-G

Position:

chr12-132677696-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006231.4(POLE):c.602T>C(p.Ile201Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,146 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 2 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.77

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007885516).

BP6

Variant 12-132677696-A-G is Benign according to our data. Variant chr12-132677696-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240580.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000722 (11/152310) while in subpopulation SAS AF= 0.00228 (11/4826). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.602T>C	p.Ile201Thr	missense_variant	7/49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.602T>C	p.Ile201Thr	missense_variant	7/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000266

AC:

AN:

251412

Hom.:

AF XY:

0.000419

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000116

AC:

170

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

133

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00181

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2016	This variant is denoted POLE c.602T>C at the cDNA level, p.Ile201Thr (I201T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Ile201Thr was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project and 1000 Genomes. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLE Ile201Thr occurs at a position that is not conserved and is not located in a known functional domain (Tahirov 2009, Preston 2010). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether POLE Ile201Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2022

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.80

CADD

Benign

7.6

DANN

Benign

0.29

DEOGEN2

Benign

0.044

T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.0079

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.1

N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

0.090

N;N

REVEL

Benign

0.10

Sift

Benign

0.84

T;T

Sift4G

Benign

0.66

T;T

Polyphen

0.0

B;B

Vest4

0.13

MVP

0.23

MPC

0.25

ClinPred

0.029

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.18

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

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