12-132672716-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_006231.4(POLE):​c.1597G>A​(p.Val533Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V533V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

POLE
NM_006231.4 missense

Scores

2
3
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 4.01
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 Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10785818).
BP6
Variant 12-132672716-C-T is Benign according to our data. Variant chr12-132672716-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405832.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000158 (24/152222) while in subpopulation AFR AF= 0.000555 (23/41462). AF 95% confidence interval is 0.000379. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkc.1597G>A p.Val533Met missense_variant 15/49 ENST00000320574.10 NP_006222.2 Q07864

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkc.1597G>A p.Val533Met missense_variant 15/491 NM_006231.4 ENSP00000322570.5 Q07864

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152222
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000555
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000399
AC:
10
AN:
250626
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135668
show subpopulations
Gnomad AFR exome
AF:
0.000497
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.0000997
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:
0.0000137
AC:
20
AN:
1461820
Hom.:
0
Cov.:
33
AF XY:
0.00000688
AC XY:
5
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.000388
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.000555
Gnomad4 AMR
AF:
0.0000654
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
Alfa
AF:
0.0000987
Hom.:
0
Bravo
AF:
0.000193
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The POLE p.Val533Met variant was not identified in the literature but was found in dbSNP (ID: rs374140892), ClinVar (classified as a VUS by Invitae and Ambry Genetics) and Cosmic (FATHMM predicted pathogenic; score=0.97). The variant was also identified in control databases in 13 of 282016 chromosomes at a frequency of 0.000046 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 11 of 24814 chromosomes (freq: 0.000443), Ashkenazi Jewish in 1 of 10322 chromosomes (freq: 0.000097) and Latino in 1 of 35400 chromosomes (freq: 0.000028), while the variant was not observed in the East Asian, European (Finnish), European (non-Finnish), Other, and South Asian populations. The p.Val533 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 25, 2024In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with cervical, breast, and/or thyroid cancer (PMID: 32098697, 35534704); This variant is associated with the following publications: (PMID: 31240875, 32098697, 36315513, 35534704) -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -
Colorectal cancer, susceptibility to, 12 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalJul 11, 2023The POLE c.1597G>A (p.Val533Met) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been observed in a colorectal tumor that did not exhibit a hypermutator phenotype (PMID: 31240875). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
POLE-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 13, 2024The POLE c.1597G>A variant is predicted to result in the amino acid substitution p.Val533Met. This variant along with c.6751T>C, p.Phe2251Leu in POLE, as well as pathogenic variants in PIK3CA and PTEN genes was found in dysplastic and invasive tumor components obtained from a cervical cancer specimen (Table 1, Vormittag-Nocito et al. 2020. PubMed ID: 32098697). This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD. In ClinVar, this variant is interpreted as likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/405832/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 23, 2024The p.V533M variant (also known as c.1597G>A), located in coding exon 15 of the POLE gene, results from a G to A substitution at nucleotide position 1597. The valine at codon 533 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingMendelicsJan 23, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T;.
Eigen
Benign
-0.032
Eigen_PC
Benign
0.069
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.0085
T
MetaRNN
Benign
0.11
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.1
M;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.13
Sift
Benign
0.12
T;T
Sift4G
Benign
0.082
T;T
Polyphen
0.064
B;B
Vest4
0.38
MVP
0.31
MPC
0.25
ClinPred
0.050
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.049
gMVP
0.49

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: rs374140892; hg19: chr12-133249302; COSMIC: COSV57691692; API