12-132638132-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_006231.4(POLE):​c.5560G>A​(p.Ala1854Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.20
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 Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.112074465).
BP6
Variant 12-132638132-C-T is Benign according to our data. Variant chr12-132638132-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473741.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLENM_006231.4 linkc.5560G>A p.Ala1854Thr missense_variant Exon 41 of 49 ENST00000320574.10 NP_006222.2 Q07864
POLEXM_011534795.4 linkc.5560G>A p.Ala1854Thr missense_variant Exon 41 of 48 XP_011533097.1
POLEXM_011534797.4 linkc.4639G>A p.Ala1547Thr missense_variant Exon 33 of 40 XP_011533099.1
POLEXM_011534802.4 linkc.2548G>A p.Ala850Thr missense_variant Exon 17 of 24 XP_011533104.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkc.5560G>A p.Ala1854Thr missense_variant Exon 41 of 49 1 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151914
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251194
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135788
show subpopulations
Gnomad AFR exome
AF:
0.000123
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461346
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
726994
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:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152032
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1854 of the POLE protein (p.Ala1854Thr). This variant is present in population databases (rs557167678, gnomAD 0.01%). 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: 473741). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

May 16, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Benign:1
Mar 29, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
T;.
Eigen
Benign
-0.28
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.64
D
LIST_S2
Benign
0.83
T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.11
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L;.
PrimateAI
Benign
0.43
T
PROVEAN
Uncertain
-2.4
N;N
REVEL
Benign
0.076
Sift
Benign
0.070
T;T
Sift4G
Benign
0.20
T;T
Polyphen
0.94
P;.
Vest4
0.21
MutPred
0.67
Gain of catalytic residue at R1858 (P = 0.0441);.;
MVP
0.31
MPC
0.42
ClinPred
0.40
T
GERP RS
2.8
Varity_R
0.054
gMVP
0.39

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.

Other links and lift over

dbSNP: rs557167678; hg19: chr12-133214718; API