chr12-132632383-G-A

Variant summary

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

The NM_006231.4(POLE):​c.6262C>T​(p.Pro2088Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,030 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 (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

6
10
3

Clinical Significance

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

Conservation

PhyloP100: 9.89
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.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkuse as main transcriptc.6262C>T p.Pro2088Ser missense_variant 45/49 ENST00000320574.10 NP_006222.2
POLEXM_011534795.4 linkuse as main transcriptc.6262C>T p.Pro2088Ser missense_variant 45/48 XP_011533097.1
POLEXM_011534797.4 linkuse as main transcriptc.5341C>T p.Pro1781Ser missense_variant 37/40 XP_011533099.1
POLEXM_011534802.4 linkuse as main transcriptc.3250C>T p.Pro1084Ser missense_variant 21/24 XP_011533104.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.6262C>T p.Pro2088Ser missense_variant 45/491 NM_006231.4 ENSP00000322570 P1

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152234
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251446
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000791
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000335
AC:
49
AN:
1461796
Hom.:
0
Cov.:
34
AF XY:
0.0000385
AC XY:
28
AN XY:
727212
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:
0.0000423
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152234
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74372
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:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000563
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 06, 2017The p.Pro2088Ser variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 3/66716 of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs749342382). Computational prediction tools and conservation analysis do n ot provide strong support for or against an impact to the protein. In summary, t he clinical significance of the p.Pro2088Ser variant is uncertain. -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 01, 2024Variant summary: POLE c.6262C>T (p.Pro2088Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251446 control chromosomes, predominantly at a frequency of 7.9e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6262C>T has been reported in the literature in individuals affected with HNPCC (Henn_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30680046). ClinVar contains an entry for this variant (Variation ID: 240589). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 14, 2024This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2088 of the POLE protein (p.Pro2088Ser). This variant is present in population databases (rs749342382, gnomAD 0.009%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 30680046). ClinVar contains an entry for this variant (Variation ID: 240589). 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 10, 2023In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer (PMID: 30680046); This variant is associated with the following publications: (PMID: 30680046) -
POLE-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 23, 2024The POLE c.6262C>T variant is predicted to result in the amino acid substitution p.Pro2088Ser. This variant was reported in one individual with personal and family history of colorectal cancer (Table S4, Henn et al. 2019. PubMed ID: 30680046). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted in ClinVar as uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/240589/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Benign
-0.0019
T
BayesDel_noAF
Uncertain
-0.040
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.79
D;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.023
T
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Uncertain
-0.0073
T
MutationAssessor
Pathogenic
3.7
H;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-4.2
D;D
REVEL
Uncertain
0.44
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
0.90
P;.
Vest4
0.86
MutPred
0.63
Gain of catalytic residue at E2085 (P = 0.0457);.;
MVP
0.81
MPC
0.75
ClinPred
0.98
D
GERP RS
5.3
Varity_R
0.26
gMVP
0.80

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: rs749342382; hg19: chr12-133208969; COSMIC: COSV57680735; COSMIC: COSV57680735; API