chr12-132632383-G-A
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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
NM_006231.4 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 9.89
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 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 |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6262C>T | p.Pro2088Ser | missense_variant | 45/49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.6262C>T | p.Pro2088Ser | missense_variant | 45/48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.5341C>T | p.Pro1781Ser | missense_variant | 37/40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.3250C>T | p.Pro1084Ser | missense_variant | 21/24 | XP_011533104.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6262C>T | p.Pro2088Ser | missense_variant | 45/49 | 1 | NM_006231.4 | ENSP00000322570 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152234Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251446Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135896
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GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461796Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28AN XY: 727212
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74372
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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 submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 06, 2017 | The 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 submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 01, 2024 | Variant 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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 14, 2024 | This 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 submitter | clinical testing | GeneDx | Oct 10, 2023 | In 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 provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 23, 2024 | The 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;.
Vest4
MutPred
Gain of catalytic residue at E2085 (P = 0.0457);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at