12-132639287-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_006231.4(POLE):c.5390G>T(p.Ser1797Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,816 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. S1797N) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5390G>T | p.Ser1797Ile | missense_variant | 40/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.5390G>T | p.Ser1797Ile | missense_variant | 40/48 | ||
POLE | XM_011534797.4 | c.4469G>T | p.Ser1490Ile | missense_variant | 32/40 | ||
POLE | XM_011534802.4 | c.2378G>T | p.Ser793Ile | missense_variant | 16/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.5390G>T | p.Ser1797Ile | missense_variant | 40/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461626Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727074
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2023 | This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1797 of the POLE protein (p.Ser1797Ile). This variant is not present in population databases (gnomAD no frequency). 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: 1223568). 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 not expected to disrupt POLE protein function. 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 | GeneDx | Jan 22, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2024 | The p.S1797I variant (also known as c.5390G>T), located in coding exon 40 of the POLE gene, results from a G to T substitution at nucleotide position 5390. The serine at codon 1797 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at