12-132624755-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006231.4(POLE):​c.6803C>G​(p.Ser2268Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

POLE
NM_006231.4 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.56
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLENM_006231.4 linkc.6803C>G p.Ser2268Trp missense_variant Exon 49 of 49 ENST00000320574.10 NP_006222.2 Q07864

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkc.6803C>G p.Ser2268Trp missense_variant Exon 49 of 49 1 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Mar 18, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 2268 of the POLE protein (p.Ser2268Trp). -

Hereditary cancer-predisposing syndrome Uncertain:1
Feb 08, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.S2268W variant (also known as c.6803C>G), located in coding exon 49 of the POLE gene, results from a C to G substitution at nucleotide position 6803. The serine at codon 2268 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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
0.15
BayesDel_addAF
Benign
-0.096
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.52
D;.
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.022
T
MetaRNN
Uncertain
0.45
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L;.
PrimateAI
Benign
0.39
T
PROVEAN
Uncertain
-4.0
D;D
REVEL
Benign
0.15
Sift
Uncertain
0.0070
D;D
Sift4G
Uncertain
0.015
D;D
Polyphen
0.98
D;.
Vest4
0.47
MutPred
0.45
Gain of catalytic residue at S2268 (P = 0.0028);.;
MVP
0.57
MPC
0.51
ClinPred
0.95
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.37
gMVP
0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-133201341; COSMIC: COSV57684827; COSMIC: COSV57684827; API