12-132673611-C-T
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_006231.4(POLE):c.1323G>A(p.Pro441=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,613,658 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0017 ( 6 hom., cov: 33)
Exomes 𝑓: 0.0018 ( 80 hom. )
Consequence
POLE
NM_006231.4 synonymous
NM_006231.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -2.65
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=-0.77).
BP6
?
Variant 12-132673611-C-T is Benign according to our data. Variant chr12-132673611-C-T is described in ClinVar as [Benign]. Clinvar id is 240387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132673611-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=-2.65 with no splicing effect.
BA1
?
GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.1323G>A | p.Pro441= | synonymous_variant | 13/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.1323G>A | p.Pro441= | synonymous_variant | 13/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00172 AC: 262AN: 152220Hom.: 6 Cov.: 33
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GnomAD3 exomes AF: 0.00327 AC: 821AN: 250918Hom.: 17 AF XY: 0.00302 AC XY: 410AN XY: 135690
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ClinVar
Significance: Benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:8
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 04, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 10, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 12, 2018 | 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, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 25, 2019 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 28, 2017 | Variant summary: The POLE c.1323G>A (p.Pro441Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 424/121124 control chromosomes (15 homozygotes), predominantly observed in the East Asian subpopulation at a frequency of 0.047923 (413/8618). This frequency is about 3374 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 02, 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 | May 01, 2018 | - - |
Polymerase proofreading-related adenomatous polyposis Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLE p.Pro441= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs116573514) as "With Benign allele ", ClinVar (classified as benign in Invitae, GeneDx, Ambry Genetics and two clinical laboratories), and in Cosmic (1x in Large intestine), databases. The variant was identified in control databases in 834 of 276646 chromosomes (18 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24014 chromosomes (freq: 0.00004), Other in 6 of 6460 chromosomes (freq: 0.0009), Latino in 1 of 34414 chromosomes (freq: 0.00003), European in 8 of 126608 chromosomes (freq: 0.00006), East Asian in 802 of 18866 chromosomes (freq: 0.04), and South Asian in 16 of 30782 chromosomes (freq: 0.0005), while the variant was not observed in the Ashkenazi Jewish, and Finnish, populations. The p.Pro441= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at