rs751451482
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_006231.4(POLE):c.1957G>T(p.Ala653Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,014 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. A653V) has been classified as Uncertain significance.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.1957G>T | p.Ala653Ser | missense_variant | 18/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.1957G>T | p.Ala653Ser | missense_variant | 18/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152214Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461800Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727182
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 653 of the POLE protein (p.Ala653Ser). This variant is present in population databases (rs751451482, gnomAD 0.02%). 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: 421176). 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 | Feb 21, 2023 | 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 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 08, 2016 | The p.Ala653Ser variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 2/10378 African chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs751451482). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Ala635Ser variant is uncertain - |
Colorectal cancer, susceptibility to, 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 19, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 17, 2023 | The p.A653S variant (also known as c.1957G>T), located in coding exon 18 of the POLE gene, results from a G to T substitution at nucleotide position 1957. The alanine at codon 653 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