chr12-132625709-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006231.4(POLE):​c.6593C>T​(p.Ala2198Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2198D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

POLE
NM_006231.4 missense

Scores

19

Clinical Significance

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

Conservation

PhyloP100: -0.489
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09200925).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
POLENM_006231.4 linkuse as main transcriptc.6593C>T p.Ala2198Val missense_variant 47/49 ENST00000320574.10
POLEXM_011534795.4 linkuse as main transcriptc.6593C>T p.Ala2198Val missense_variant 47/48
POLEXM_011534797.4 linkuse as main transcriptc.5672C>T p.Ala1891Val missense_variant 39/40
POLEXM_011534802.4 linkuse as main transcriptc.3581C>T p.Ala1194Val missense_variant 23/24

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.6593C>T p.Ala2198Val missense_variant 47/491 NM_006231.4 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
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:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 14, 2019Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 12, 2024This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2198 of the POLE protein (p.Ala2198Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 1306537). 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 not expected to disrupt POLE protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
0.60
DANN
Benign
0.84
DEOGEN2
Benign
0.082
T;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.067
N
LIST_S2
Benign
0.56
T;T
M_CAP
Benign
0.0036
T
MetaRNN
Benign
0.092
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L;.
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.70
N;N
REVEL
Benign
0.010
Sift
Benign
0.26
T;T
Sift4G
Benign
0.33
T;T
Polyphen
0.0
B;.
Vest4
0.096
MutPred
0.47
Gain of catalytic residue at Y2194 (P = 0.0029);.;
MVP
0.18
MPC
0.19
ClinPred
0.050
T
GERP RS
-0.83
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.034
gMVP
0.16

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: chr12-133202295; API