rs572252265
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting
The NM_006231.4(POLE):c.6271C>T(p.Pro2091Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6271C>T | p.Pro2091Ser | missense_variant | Exon 45 of 49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.6271C>T | p.Pro2091Ser | missense_variant | Exon 45 of 48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.5350C>T | p.Pro1784Ser | missense_variant | Exon 37 of 40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.3259C>T | p.Pro1087Ser | missense_variant | Exon 21 of 24 | XP_011533104.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251412Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135878
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461838Hom.: 0 Cov.: 34 AF XY: 0.0000536 AC XY: 39AN XY: 727224
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
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This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2091 of the POLE protein (p.Pro2091Ser). This variant is present in population databases (rs572252265, gnomAD 0.06%). 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: 473789). 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 supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Colorectal cancer, susceptibility to, 12 Uncertain:1
The missense c.6271C>T p.Pro2091Ser variant in the POLE gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genom This variant is reported with the allele frequency 0.007% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Proline at position 2091 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Pro2091Ser in POLE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.P2091S variant (also known as c.6271C>T), located in coding exon 45 of the POLE gene, results from a C to T substitution at nucleotide position 6271. The proline at codon 2091 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at