rs747676884
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_006231.4(POLE):c.6734C>G(p.Thr2245Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,946 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. T2245A) has been classified as Uncertain significance.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6734C>G | p.Thr2245Ser | missense_variant | 48/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6734C>G | p.Thr2245Ser | missense_variant | 48/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152254Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250870Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135704
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461574Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727122
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152372Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74520
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 19, 2023 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 2245 of the POLE protein (p.Thr2245Ser). This variant is present in population databases (rs747676884, gnomAD 0.003%). 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: 473811). 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 | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 19, 2020 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 22, 2021 | The p.T2245S variant (also known as c.6734C>G), located in coding exon 48 of the POLE gene, results from a C to G substitution at nucleotide position 6734. The threonine at codon 2245 is replaced by serine, 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. - |
Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 28, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at