chr12-132673664-G-C
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_006231.4(POLE):āc.1270C>Gā(p.Leu424Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,680 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 Pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
POLE
NM_006231.4 missense
NM_006231.4 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 6.86
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 Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.957
PP5
Variant 12-132673664-G-C is Pathogenic according to our data. Variant chr12-132673664-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132673664-G-C is described in Lovd as [Pathogenic]. Variant chr12-132673664-G-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| POLE | NM_006231.4 | c.1270C>G | p.Leu424Val | missense_variant | 13/49 | ENST00000320574.10 | NP_006222.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| POLE | ENST00000320574.10 | c.1270C>G | p.Leu424Val | missense_variant | 13/49 | 1 | NM_006231.4 | ENSP00000322570.5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461680Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727168
GnomAD4 exome
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34
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 19, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 424 of the POLE protein (p.Leu424Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal adenomas and carcinomas (PMID: 23263490, 24501277, 25370038, 25529843, 27683556). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40046). 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 expected to disrupt POLE protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2017 | This pathogenic variant is denoted POLE c.1270C>G at the cDNA level, p.Leu424Val (L424V) at the protein level, and results in the change of a Leucine to a Valine (CTC>GTC). POLE Leu424Val has been observed in multiple individuals with either an attenuated polyposis phenotype or a history of early onset colorectal cancer, with de novo occurrence reported in two individuals (Palles 2013, Elsayed 2014, Chubb 2015). Additionally, Spier et al. (2014) found this variant to segregate with polyposis and/or colorectal cancer diagnoses in three families. While functional assays have not specifically interrogated POLE Leu424Val, the equivalent residue has been found to have an important role in exonuclease activity in both bacteriophage and yeast systems (Hogg 2004, Murphy 2006). POLE Leu424Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. POLE Leu424Val occurs at a position that is conserved across species and is located in the Exo IV motif of the Exonuclease Domain (Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic. - |
Cystic fibrosis-gastritis-megaloblastic anemia syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2021 | Variant summary: POLE c.1270C>G (p.Leu424Val) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251340 control chromosomes. c.1270C>G has been reported in the literature in multiple individuals affected with Colorectal Cancer or adenomas (e.g. Palles_2013, Chubb_2015, Elsayed_2015, Hamzaoui_2020), including at least one-de novo occurrence (e.g. Valle_2014), as well a co-segregation with disease in multiple families (e.g. Palles_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence indicating that the variant results in a significantly increased mutation rate as assessed by yeast fluctuation assays (e.g. Castellsague_2018, Hamzaoui_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic or risk factor. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 06, 2024 | The p.L424V pathogenic mutation (also known as c.1270C>G), located in coding exon 13 of the POLE gene, results from a C to G substitution at nucleotide position 1270. The leucine at codon 424 is replaced by valine, an amino acid with highly similar properties. This highly conserved residue is in the active site of the exonuclease domain of the POLE protein, and this alteration is predicted to affect the nuclear activity by distorting the packing of helices involved in the exonuclease active site (Palles C et al. Nat. Genet. 2013 Feb; 45(2):136-44). This mutation has been reported as one of the most commonly identified POLE mutations in familial colorectal cancer and polyposis patients. It has been shown to segregate with disease in multiple unrelated families and has not been reported in over six thousand controls or in population cohorts. In addition it has been reported as a de novo occurrence in two individuals (Spier I et al. Int. J. Cancer. 2015 Jul;137(2):320-31; Palles C et al. Nat. Genet. 2013 Feb; 45(2):136-44. Valle L et al. Hum. Mol. Genet. 2014 Jul; 23(13):3506-12. Elsayed FA et al. Eur. J. Hum. Genet. 2015 Aug; 23(8):1080-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Colorectal cancer, susceptibility to, 12 Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Aug 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of catalytic residue at N423 (P = 0);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at