chr12-132665430-C-T
Variant names:
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_006231.4(POLE):c.2340G>A(p.Ser780Ser) 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 (★★).
Frequency
Genomes: 𝑓 0.021 ( 51 hom., cov: 31)
Exomes 𝑓: 0.023 ( 480 hom. )
Consequence
POLE
NM_006231.4 synonymous
NM_006231.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.78
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 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
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0207 AC: 3153AN: 152138Hom.: 51 Cov.: 31
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GnomAD3 exomes AF: 0.0235 AC: 5866AN: 249490Hom.: 85 AF XY: 0.0241 AC XY: 3261AN XY: 135096
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GnomAD4 exome AF: 0.0234 AC: 34091AN: 1459322Hom.: 480 Cov.: 31 AF XY: 0.0237 AC XY: 17200AN XY: 726062
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GnomAD4 genome AF: 0.0207 AC: 3151AN: 152256Hom.: 51 Cov.: 31 AF XY: 0.0215 AC XY: 1600AN XY: 74436
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ClinVar
Significance: Benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:7
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2016 | This 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 provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 28, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 24, 2016 | Variant 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 submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2025 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 19, 2015 | This 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. - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Feb 28, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jan 20, 2025 | The synonymous variant NM_006231.4(POLE):c.2340G>A (p.Ser780=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380225 as of 2025-01-02). The p.Ser780= variant is observed in 107/5,008 (2.1366%) alleles from individuals of 1kG All background in 1kG, indicating it is a common benign variant. The p.Ser780= variant is not predicted to disrupt an existing splice site. The p.Ser780= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign. - |
Colorectal cancer, susceptibility to, 12 Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Carcinoma of colon Benign:1
Benign, no assertion criteria provided | clinical testing | Department 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. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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