12-132639170-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_006231.4(POLE):c.5507C>T(p.Ala1836Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,614,052 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. A1836S) 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.5507C>T | p.Ala1836Val | missense_variant | 40/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.5507C>T | p.Ala1836Val | missense_variant | 40/48 | ||
POLE | XM_011534797.4 | c.4586C>T | p.Ala1529Val | missense_variant | 32/40 | ||
POLE | XM_011534802.4 | c.2495C>T | p.Ala832Val | missense_variant | 16/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.5507C>T | p.Ala1836Val | missense_variant | 40/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251432Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37AN XY: 727236
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29641532) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1836 of the POLE protein (p.Ala1836Val). This variant is present in population databases (rs780776704, gnomAD 0.002%). 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: 240561). 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 with a negative 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2021 | The p.A1836V variant (also known as c.5507C>T), located in coding exon 40 of the POLE gene, results from a C to T substitution at nucleotide position 5507. The alanine at codon 1836 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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