12-132642881-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4
The NM_006231.4(POLE):c.4667G>A(p.Arg1556Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000669 in 1,613,768 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. R1556L) 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
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 250962Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135660
GnomAD4 exome AF: 0.0000725 AC: 106AN: 1461564Hom.: 0 Cov.: 34 AF XY: 0.0000867 AC XY: 63AN XY: 727060
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1556 of the POLE protein (p.Arg1556Gln). This variant is present in population databases (rs762965148, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of POLE-related conditions (PMID: 32792570). ClinVar contains an entry for this variant (Variation ID: 240533). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
not specified Uncertain:1
Variant summary: POLE c.4667G>A (p.Arg1556Gln) results in a conservative amino acid change located in the DNA polymerase epsilon, catalytic subunit A, C-terminal domain (IPR013697) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250962 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLE causing Facial Dysmorphism, Immunodeficiency, Livedo, and Short Stature (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.4667G>A has been reported in the literature in individuals affected with Hereditary Non-polyposis Colorectal Cancer (Mur_2020) or with triple-negative breast cancer (Bhai_2021), including in the presence of an alternate pathogenic variant. These report(s) do not provide unequivocal conclusions about association of the variant with Facial Dysmorphism, Immunodeficiency, Livedo, And Short Stature. The following publications have been ascertained in the context of this evaluation (PMID: 32792570, 34326862). ClinVar contains an entry for this variant (Variation ID: 240533). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Polymerase proofreading-related adenomatous polyposis Uncertain:1
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POLE-related disorder Uncertain:1
The POLE c.4667G>A variant is predicted to result in the amino acid substitution p.Arg1556Gln. This variant was reported in an individual with epithelial ovarian cancer (Song et al. 2021. PubMed ID: 32546565, Supplementary Table 6). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/240533/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.R1556Q variant (also known as c.4667G>A), located in coding exon 36 of the POLE gene, results from a G to A substitution at nucleotide position 4667. The arginine at codon 1556 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at