12-132660983-C-T

Position:

chr12-132660983-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_006231.4(POLE):c.3046G>A(p.Val1016Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,611,244 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1016V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:8

Conservation

PhyloP100: 7.77

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10815844).

BP6

Variant 12-132660983-C-T is Benign according to our data. Variant chr12-132660983-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220916.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3, Benign=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00105 (1538/1459004) while in subpopulation NFE AF= 0.00127 (1412/1110562). AF 95% confidence interval is 0.00122. There are 1 homozygotes in gnomad4_exome. There are 717 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.3046G>A	p.Val1016Met	missense_variant	25/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.3046G>A	p.Val1016Met	missense_variant	25/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000777

AC:

193

AN:

248236

Hom.:

AF XY:

0.000775

AC XY:

104

AN XY:

134158

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000375

Gnomad NFE exome

AF:

0.00153

Gnomad OTH exome

AF:

0.000990

GnomAD4 exome

AF:

0.00105

AC:

1538

AN:

1459004

Hom.:

Cov.:

AF XY:

0.000988

AC XY:

717

AN XY:

725734

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000203

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000658

Gnomad4 NFE exome

AF:

0.00127

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.000644

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000914

Hom.:

Bravo

AF:

0.000589

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000972

AC:

118

EpiCase

AF:

0.00120

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 26, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 29, 2020	This variant is associated with the following publications: (PMID: 28873162, 21701589, 29458332) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	POLE: BS1 -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 31, 2016	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: This variant has not been reported in affected individuals. It is classified in ClinVar with 1 star as Likely benign by Invitae and VUS by GeneDx. It is present in ExAC at a MaxMAF of 0.15% (high for disease incidence and gene contribution). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 14, 2019	Variant summary: POLE c.3046G>A (p.Val1016Met) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain (IPR006134) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 248236 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 55 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. c.3046G>A has been reported in the literature in individuals affected with various tumor phenotypes, e.g. colorectal cancer and cutaneous melanoma, but without strong evidence of causality (Dominguez-Valentin_2018, Pritchard_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one classified as likely benign while the others classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 27, 2024	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 15, 2021	- -

Colorectal cancer, susceptibility to, 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLE p.Val1016Met variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs147692158) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹ and ClinVar (as likely benign by Invitae, and uncertain significance by GeneDx, Laboratory for Molecular Medicine Partners Health Care Personalized Medicine, Quest Diagnostics and Ambry Genetics). The variant was identified in control databases in 206 of 273880 chromosomes (1 homozygous) at a frequency of 0.0008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 5 of 24010 chromosomes (freq: 0.0002), Other in 6 of 6400 chromosomes (freq: 0.0009), Latino in 8 of 34170 chromosomes (freq: 0.0002), European (Non-Finnish) in 172 of 124734 chromosomes (freq: 0.001), Finnish in 15 of 25468 chromosomes (freq: 0.0006); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Val1016 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

POLE-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.0090

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.18

Sift

Benign

0.057

T;T

Sift4G

Uncertain

0.051

T;T

Polyphen

0.48

P;P

Vest4

0.78

MVP

0.31

MPC

1.6

ClinPred

0.10

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.51

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