rs749342382
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_006231.4(POLE):c.6262C>T(p.Pro2088Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,030 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. P2088L) 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.6262C>T | p.Pro2088Ser | missense_variant | 45/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.6262C>T | p.Pro2088Ser | missense_variant | 45/48 | ||
POLE | XM_011534797.4 | c.5341C>T | p.Pro1781Ser | missense_variant | 37/40 | ||
POLE | XM_011534802.4 | c.3250C>T | p.Pro1084Ser | missense_variant | 21/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6262C>T | p.Pro2088Ser | missense_variant | 45/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251446Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135896
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461796Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28AN XY: 727212
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74372
ClinVar
Submissions by phenotype
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 07, 2019 | Variant summary: POLE c.6262C>T (p.Pro2088Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 282858 control chromosomes, predominantly at a frequency of 8.5e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.6262C>T, has been reported in the literature in individuals affected with HNPCC (Henn_2019). This report does not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 06, 2017 | The p.Pro2088Ser variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 3/66716 of European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs749342382). Computational prediction tools and conservation analysis do n ot provide strong support for or against an impact to the protein. In summary, t he clinical significance of the p.Pro2088Ser variant is uncertain. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2088 of the POLE protein (p.Pro2088Ser). This variant is present in population databases (rs749342382, gnomAD 0.009%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 30680046). ClinVar contains an entry for this variant (Variation ID: 240589). 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 | Oct 10, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colon cancer (PMID: 30680046); This variant is associated with the following publications: (PMID: 30680046) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at