rs369549727
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_006231.4(POLE):c.6493C>T(p.Arg2165Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000807 in 1,610,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R2165H) has been classified as Benign.
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6493C>T | p.Arg2165Cys | missense_variant | 46/49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.6493C>T | p.Arg2165Cys | missense_variant | 46/48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.5572C>T | p.Arg1858Cys | missense_variant | 38/40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.3481C>T | p.Arg1161Cys | missense_variant | 22/24 | XP_011533104.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6493C>T | p.Arg2165Cys | missense_variant | 46/49 | 1 | NM_006231.4 | ENSP00000322570.5 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000287 AC: 7AN: 243964Hom.: 0 AF XY: 0.0000303 AC XY: 4AN XY: 132068
GnomAD4 exome AF: 0.00000686 AC: 10AN: 1457824Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 724914
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74332
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2023 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19296856) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2165 of the POLE protein (p.Arg2165Cys). This variant is present in population databases (rs369549727, gnomAD 0.005%). 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: 240597). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 22, 2018 | The p.Arg2165Cys variant in POLE has not been previously reported in the literat ure in individuals with colorectal cancer but has been reported by other clinica l laboratories in ClinVar (Variation ID 240597). It has also been identified in 1/18498 East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org; dbSN P rs369549727). Computational prediction tools and conservation analysis suggest that the p.Arg2165Cys variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, the clinical sig nificance of the p.Arg2165Cys variant is uncertain. ACMG/AMP Criteria applied: P P3, PM2. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at