rs753627422
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_006231.4(POLE):c.5467C>T(p.Arg1823Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,820 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 (★★).
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.5467C>T | p.Arg1823Cys | missense_variant | Exon 40 of 49 | ENST00000320574.10 | NP_006222.2 | |
POLE | XM_011534795.4 | c.5467C>T | p.Arg1823Cys | missense_variant | Exon 40 of 48 | XP_011533097.1 | ||
POLE | XM_011534797.4 | c.4546C>T | p.Arg1516Cys | missense_variant | Exon 32 of 40 | XP_011533099.1 | ||
POLE | XM_011534802.4 | c.2455C>T | p.Arg819Cys | missense_variant | Exon 16 of 24 | XP_011533104.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251422Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135894
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727208
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1823 of the POLE protein (p.Arg1823Cys). This variant is present in population databases (rs753627422, gnomAD 0.006%). 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: 473733). 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 expected to disrupt POLE protein function with a positive 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; Observed in an individual with personal and/or family history of breast and/or ovarian cancer (PMID: 35534704); This variant is associated with the following publications: (PMID: 35534704) -
not specified Uncertain:1
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Hereditary cancer-predisposing syndrome Uncertain:1
The p.R1823C variant (also known as c.5467C>T), located in coding exon 40 of the POLE gene, results from a C to T substitution at nucleotide position 5467. The arginine at codon 1823 is replaced by cysteine, an amino acid with highly dissimilar 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at