rs771404261
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_006231.4(POLE):c.6350A>G(p.Asn2117Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. N2117D) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6350A>G | p.Asn2117Ser | missense_variant | 46/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.6350A>G | p.Asn2117Ser | missense_variant | 46/48 | ||
POLE | XM_011534797.4 | c.5429A>G | p.Asn1810Ser | missense_variant | 38/40 | ||
POLE | XM_011534802.4 | c.3338A>G | p.Asn1113Ser | missense_variant | 22/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6350A>G | p.Asn2117Ser | missense_variant | 46/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249898Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135294
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461398Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726984
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2117 of the POLE protein (p.Asn2117Ser). This variant is present in population databases (rs771404261, gnomAD 0.0009%). 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: 567240). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 19, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2023 | The p.N2117S variant (also known as c.6350A>G), located in coding exon 46 of the POLE gene, results from an A to G substitution at nucleotide position 6350. The asparagine at codon 2117 is replaced by serine, an amino acid with highly 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