rs199746481

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_006231.4(POLE):c.1138G>T(p.Gly380Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G380R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 7.87

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4 linkuse as main transcript	c.1138G>T	p.Gly380Cys	missense_variant	12/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10 linkuse as main transcript	c.1138G>T	p.Gly380Cys	missense_variant	12/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251402

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	The POLE c.1138G>T; p.Gly380Cys variant (rs199746481) is reported in the literature in individuals affected with breast cancer, ovarian cancer, and polyposis (Mur 2020, Song 2021), as well as in controls (Song 2021). This variant is reported in ClinVar (Variation ID: 240378) and is found in the general population with an overall allele frequency of 0.0028% (8/282,780 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.531). However, functional analyses in a yeast-based exonuclease repair assay demonstrate increased mutation rate (Mur 2020). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Mur P et al. Role of POLE and POLD1 in familial cancer. Genet Med. 2020 Dec;22(12):2089-2100. PMID: 32792570. Song H et al. Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer. J Med Genet. 2021 May;58(5):305-313. PMID: 32546565. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 11, 2022	The frequency of this variant in the general population, 0.000046 (6/129122 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer and polyps (PMID: 32792570 (2020)). A yeast based functional assay has shown that this variant may have a deleterious impact on POLE function (PMID: 32792570 (2020)). However, further studies are needed to validate this finding. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrated a damaging effect: increased mutation rate and intermediate revertant colonies in a yeast-based exonuclease repair activity assay (PMID: 32792570); Observed in individuals with breast cancer, polyps, and ovarian cancer, but also in unaffected controls (PMID: 32792570, 32546565); This variant is associated with the following publications: (PMID: 32792570, 32546565, 20951805) -

Colorectal cancer, susceptibility to, 12

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 09, 2022	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 380 of the POLE protein (p.Gly380Cys). This variant is present in population databases (rs199746481, gnomAD 0.008%). This missense change has been observed in individual(s) with polyps (PMID: 32792570). ClinVar contains an entry for this variant (Variation ID: 240378). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLE protein function. Experimental studies have shown that this missense change affects POLE function (PMID: 32792570). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2022

The p.G380C variant (also known as c.1138G>T), located in coding exon 12 of the POLE gene, results from a G to T substitution at nucleotide position 1138. The glycine at codon 380 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified once in a cohort of ovarian cancer cases, but was also identified in three control individuals (Song H et al. J Med Genet, 2021 05;58:305-313). In another study, this variant was identified in 2/2813 unrelated individuals undergoing multigene panel testing for hereditary cancer and one was diagnosed with breast cancer (x2) at age 61 while the other was diagnosed with 10-20 polyps at age 72 (Mur P et al. Genet Med, 2020 12;22:2089-2100). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.022

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

0.0091

MutationAssessor

Pathogenic

3.0

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.88

MutPred

0.63

Gain of catalytic residue at S382 (P = 0);.;

MVP

0.64

MPC

0.80

ClinPred

0.96

GERP RS

5.9

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.58

gMVP

0.83

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