12-132649021-T-C

Position:

chr12-132649021-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006231.4(POLE):c.4057A>G(p.Ser1353Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000766 in 1,613,788 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 2 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:13

Conservation

PhyloP100: 7.93

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:

POLE (HGNC:):

POLE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012595266).

BP6

Variant 12-132649021-T-C is Benign according to our data. Variant chr12-132649021-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240500.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=3, Benign=1}. Variant chr12-132649021-T-C is described in Lovd as [Likely_benign].

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.4057A>G	p.Ser1353Gly	missense_variant	32/49	ENST00000320574.10	NP_006222.2	Q07864

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.4057A>G	p.Ser1353Gly	missense_variant	32/49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000555

AC:

139

AN:

250366

Hom.:

AF XY:

0.000517

AC XY:

AN XY:

135444

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00159

Gnomad NFE exome

AF:

0.000805

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000785

AC:

1147

AN:

1461540

Hom.:

Cov.:

AF XY:

0.000708

AC XY:

515

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00154

Gnomad4 NFE exome

AF:

0.000923

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000585

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000759

Hom.:

Bravo

AF:

0.000574

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2021	This variant is associated with the following publications: (PMID: 22885699) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 07, 2023	The POLE c.4057A>G; p.Ser1353Gly variant (rs141619382) is reported in the literature in individuals affected with cancer, but without clear disease association (Bhai 2021, Garmezy 2022, Mur 2020). This variant is also reported in ClinVar (Variation ID: 240500), and is found in the general population with an overall allele frequency of 0.06% (157/281776 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.168). Additionally, this variant is not located in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bhai P et al. Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. Front Genet. 2021 Jul 13;12:698595. PMID: 34326862. Garmezy B et al. Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers. JCO Precis Oncol. 2022 Feb;6:e2100267. PMID: 35108036. Mur P et al. Role of POLE and POLD1 in familial cancer. Genet Med. 2020 Dec;22(12):2089-2100. PMID: 32792570. Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. PMID: 23263490. Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516. PMID: 30523343. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	POLE: BP4, BS1:Supporting -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2023	Variant summary: POLE c.4057A>G (p.Ser1353Gly) results in a non-conservative amino acid change in 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 0.00056 in 250366 control chromosomes, predominantly at a frequency of 0.0008 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 56-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 a benign polymorphism. The variant, c.4057A>G, has been reported in the literature in individuals affected with polyposis and other tumor phenotypes (e.g. Mur_2020, Garmezy_2022), however without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is located outside of the exonuclease domain, and while missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLE protein have been known to be associated with an increased risk for colonic adenomatous polyps and colon cancer, however, missense variants outside the exonuclease domain, are unlikely to be associated with polyposis or colon cancer (see e.g. PMID: 23263490, 23447401). The following publications have been ascertained in the context of this evaluation (PMID: 32792570, 35108036). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 28, 2017	- -
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	Apr 05, 2018	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 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. -

Polymerase proofreading-related adenomatous polyposis

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The POLE p.Ser1353Gly variant was identified in 1 of 2080 proband chromosomes (frequency: 0.0005) from an individual with advanced cancer (Mandelker 2017). The variant was identified in dbSNP (rs141619382) as â€šÃ„Ãºwith other alleleâ€šÃ„Ã¹ and ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, PreventionGenetics and 1 other submitter and likely benign by Invitae and Quest Diagnostics). The variant was identified in control databases in 159 of 276,260 chromosomes at a frequency of 0.0006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 5 of 23,992 chromosomes (freq: 0.0002), Other in 4 of 6450 chromosomes (freq: 0.0006), Latino in 6 of 34,396 chromosomes (freq: 0.0002), European in 108 of 126,130 chromosomes (freq: 0.0009), Finnish in 36 of 25,534 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Ser1353 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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

Feb 16, 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). -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.092

T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

0.050

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.78

N;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.17

Sift

Benign

0.49

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0

B;B

Vest4

0.41

MVP

0.43

MPC

0.17

ClinPred

0.039

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.12

gMVP

0.24

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