12-132642551-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_006231.4(POLE):c.4907A>C(p.Tyr1636Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,302 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 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152004Hom.: 0 Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461298Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 726956
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152004Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74222
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 1636 of the POLE protein (p.Tyr1636Ser). This variant is not present in population databases (gnomAD no frequency). 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: 473698). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.Y1636S variant (also known as c.4907A>C), located in coding exon 37 of the POLE gene, results from an A to C substitution at nucleotide position 4907. The tyrosine at codon 1636 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at