rs190813054
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_006231.4(POLE):c.6716C>T(p.Ala2239Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2239E) has been classified as Uncertain significance.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6716C>T | p.Ala2239Val | missense_variant | 48/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6716C>T | p.Ala2239Val | missense_variant | 48/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000558 AC: 14AN: 250896Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135710
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461722Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29AN XY: 727182
GnomAD4 genome ? AF: 0.0000656 AC: 10AN: 152344Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74498
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a pediatric patient with neuroblastoma (Zhang et al., 2015); Observed in the homozygous state in an individual with attenuated adenomatous polyposis and did not segregate with disease in the family (Lorca et al., 2019); This variant is associated with the following publications: (PMID: 23675308, 26580448, 31285513) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2239 of the POLE protein (p.Ala2239Val). This variant is present in population databases (rs190813054, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 405644). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 19, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Carcinoma of colon Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLE p.Ala2239Val variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs190813054) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 13 of 276806 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: East Asian in 7 of 18868 chromosomes (freq: 0.000371), Latino in 4 of 34416 chromosomes (freq: 0.0001), European in 1 of 126374 chromosomes (freq: 0.00001), and South Asian in 1 of 30780 chromosomes (freq: 0.000032); it was not observed in the African, Other, Ashkenazi Jewish, and Finnish populations. The p.Ala2239 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. These computational analyses are not very predictive of 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. - |
Colorectal cancer, susceptibility to, 12 Benign:1
Likely benign, no assertion criteria provided | clinical testing | Molecular Oncology Laboratory, Hospital Clínico San Carlos | Jun 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at