rs778456846
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_006231.4(POLE):c.6460C>T(p.Pro2154Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P2154R) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6460C>T | p.Pro2154Ser | missense_variant | 46/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.6460C>T | p.Pro2154Ser | missense_variant | 46/48 | ||
POLE | XM_011534797.4 | c.5539C>T | p.Pro1847Ser | missense_variant | 38/40 | ||
POLE | XM_011534802.4 | c.3448C>T | p.Pro1150Ser | missense_variant | 22/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6460C>T | p.Pro2154Ser | missense_variant | 46/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 249988Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135258
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461208Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 726864
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2154 of the POLE protein (p.Pro2154Ser). This variant is present in population databases (rs778456846, 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: 574369). 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 | May 25, 2024 | The p.P2154S variant (also known as c.6460C>T), located in coding exon 46 of the POLE gene, results from a C to T substitution at nucleotide position 6460. The proline at codon 2154 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at