12-132632750-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_006231.4(POLE):c.6050G>A(p.Arg2017His) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,612,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. R2017C) 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.6050G>A | p.Arg2017His | missense_variant | 44/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.6050G>A | p.Arg2017His | missense_variant | 44/48 | ||
POLE | XM_011534797.4 | c.5129G>A | p.Arg1710His | missense_variant | 36/40 | ||
POLE | XM_011534802.4 | c.3038G>A | p.Arg1013His | missense_variant | 20/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6050G>A | p.Arg2017His | missense_variant | 44/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000322 AC: 8AN: 248196Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134716
GnomAD4 exome AF: 0.000124 AC: 181AN: 1460434Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 78AN XY: 726616
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74314
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2017 of the POLE protein (p.Arg2017His). This variant is present in population databases (rs144178150, gnomAD 0.01%). 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: 240582). 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 | Apr 10, 2023 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28427513) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 18, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 11, 2022 | Variant summary: POLE c.6050G>A (p.Arg2017His) results in a non-conservative amino acid change in the encoded protein sequence. Three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 248196 control chromosomes, predominantly at a frequency of 6.2e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6050G>A has been reported in the literature in individuals affected with Breast Cancer without strong evidence for causality (Zhao_2019). This report does not provide unequivocal conclusions about association of the variant with Colorectal Cancer. Co-occurrence with a pathogenic variant has been reported (CHEK2 c.1100del, p.T367MfsX15), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS. - |
Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at