12-132665430-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000320574.10(POLE):​c.2340G>A​(p.Ser780=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,611,578 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S780S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 51 hom., cov: 31)
Exomes 𝑓: 0.023 ( 480 hom. )

Consequence

POLE
ENST00000320574.10 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -3.78
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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 12-132665430-C-T is Benign according to our data. Variant chr12-132665430-C-T is described in ClinVar as [Benign]. Clinvar id is 380225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132665430-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-3.78 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0207 (3151/152256) while in subpopulation EAS AF= 0.028 (145/5180). AF 95% confidence interval is 0.0265. There are 51 homozygotes in gnomad4. There are 1600 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 51 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLENM_006231.4 linkuse as main transcriptc.2340G>A p.Ser780= synonymous_variant 21/49 ENST00000320574.10 NP_006222.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLEENST00000320574.10 linkuse as main transcriptc.2340G>A p.Ser780= synonymous_variant 21/491 NM_006231.4 ENSP00000322570 P1

Frequencies

GnomAD3 genomes
AF:
0.0207
AC:
3153
AN:
152138
Hom.:
51
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00427
Gnomad AMI
AF:
0.0164
Gnomad AMR
AF:
0.0187
Gnomad ASJ
AF:
0.0141
Gnomad EAS
AF:
0.0279
Gnomad SAS
AF:
0.0263
Gnomad FIN
AF:
0.0411
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.0275
Gnomad OTH
AF:
0.0201
GnomAD3 exomes
AF:
0.0235
AC:
5866
AN:
249490
Hom.:
85
AF XY:
0.0241
AC XY:
3261
AN XY:
135096
show subpopulations
Gnomad AFR exome
AF:
0.00375
Gnomad AMR exome
AF:
0.0119
Gnomad ASJ exome
AF:
0.0157
Gnomad EAS exome
AF:
0.0339
Gnomad SAS exome
AF:
0.0248
Gnomad FIN exome
AF:
0.0421
Gnomad NFE exome
AF:
0.0252
Gnomad OTH exome
AF:
0.0250
GnomAD4 exome
AF:
0.0234
AC:
34091
AN:
1459322
Hom.:
480
Cov.:
31
AF XY:
0.0237
AC XY:
17200
AN XY:
726062
show subpopulations
Gnomad4 AFR exome
AF:
0.00359
Gnomad4 AMR exome
AF:
0.0125
Gnomad4 ASJ exome
AF:
0.0170
Gnomad4 EAS exome
AF:
0.0290
Gnomad4 SAS exome
AF:
0.0217
Gnomad4 FIN exome
AF:
0.0419
Gnomad4 NFE exome
AF:
0.0238
Gnomad4 OTH exome
AF:
0.0213
GnomAD4 genome
AF:
0.0207
AC:
3151
AN:
152256
Hom.:
51
Cov.:
31
AF XY:
0.0215
AC XY:
1600
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.00426
Gnomad4 AMR
AF:
0.0187
Gnomad4 ASJ
AF:
0.0141
Gnomad4 EAS
AF:
0.0280
Gnomad4 SAS
AF:
0.0259
Gnomad4 FIN
AF:
0.0411
Gnomad4 NFE
AF:
0.0275
Gnomad4 OTH
AF:
0.0199
Alfa
AF:
0.0225
Hom.:
57
Bravo
AF:
0.0172
Asia WGS
AF:
0.0380
AC:
132
AN:
3478
EpiCase
AF:
0.0231
EpiControl
AF:
0.0224

ClinVar

Significance: Benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7
Benign, criteria provided, single submitterclinical testingGeneDxDec 01, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 22, 2016- -
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoOct 28, 2016- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 24, 2016Variant summary: The POLE c.2340G>A (p.Ser780Ser) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing, while ESE finder predicts alterations to ESE binding sites. However, these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2835/120810 (40 homozygotes, 1/42, frequency: 0.0234666), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic POLE variant of 1/70422 (0.0000142), suggesting this variant is likely a benign polymorphism. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, no assertion criteria providedclinical testingTrue Health DiagnosticsFeb 28, 2018- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 19, 2015This alteration is classified as 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. -
Carcinoma of colon Benign:1
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The POLE p.Ser780= variant was not identified in the literature nor was it identified in the Cosmic and MutDB. The variant was identified in dbSNP (ID: rs5744822) “With Benign ,Likely benign allele”, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x) and in control databases in 6661 (103 homozygous) of 275298 chromosomes at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 95 (1 homozygous) of 24026 chromosomes (freq: 0.004), Other in 168 (1 homozygous) of 6440 chromosomes (freq: 0.03), Latino in 414 (2 homozygous) of 34414 chromosomes (freq: 0.01), European Non-Finnish in 3414 (47 homozygous) of 126558 chromosomes (freq: 0.03), Ashkenazi Jewish in 163 (1 homozygous) of 10146 chromosomes (freq: 0.02), East Asian in 624 (12 homozygous) of 18856 chromosomes (freq: 0.03), European Finnish in 1026 (27 homozygous) of 24078 chromosomes (freq: 0.04), and South Asian in 757 (12 homozygous) of 30780 chromosomes (freq: 0.02). The p.Ser780= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Colorectal cancer, susceptibility to, 12 Benign:1
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
0.031
DANN
Benign
0.56
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs5744822; hg19: chr12-133242016; COSMIC: COSV57674221; COSMIC: COSV57674221; API