rs149777592
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_006231.4(POLE):c.3229C>T(p.Arg1077Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,613,644 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. R1077H) 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.3229C>T | p.Arg1077Cys | missense_variant | 26/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.3229C>T | p.Arg1077Cys | missense_variant | 26/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000119 AC: 18AN: 151672Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000757 AC: 19AN: 251104Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135784
GnomAD4 exome AF: 0.000150 AC: 219AN: 1461854Hom.: 0 Cov.: 32 AF XY: 0.000147 AC XY: 107AN XY: 727238
GnomAD4 genome ? AF: 0.000119 AC: 18AN: 151790Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10AN XY: 74238
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 10, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1077 of the POLE protein (p.Arg1077Cys). This variant is present in population databases (rs149777592, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 405597). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal and other cancers (Zhang et al., 2015; Mandelker et al., 2017; Raskin et al., 2017); This variant is associated with the following publications: (PMID: 26580448, 25194279, 28166811, 28873162, 29212164, 29338072) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 19, 2015 | The p.R1077C variant (also known as c.3229C>T), located in coding exon 26 of the POLE gene, results from a C to T substitution at nucleotide position 3229. The arginine at codon 1077 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was previously reported in the SNPDatabase as rs149777592. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.02% (2/13006) total alleles studied and 0.02% (2/8600) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at