12-132643929-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_006231.4(POLE):c.4198T>C(p.Tyr1400His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152018Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251422Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135878
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461792Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727204
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152018Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74260
ClinVar
Submissions by phenotype
not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in a patient undergoing multi-gene panel testing for personal and family history of cancer (PMID: 34326862); This variant is associated with the following publications: (PMID: 34326862) -
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1400 of the POLE protein (p.Tyr1400His). This variant is present in population databases (rs761011442, gnomAD 0.002%). This missense change has been observed in individual(s) with melanoma (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 405738). 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) has been performed 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. -
not specified Uncertain:1
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POLE-related disorder Uncertain:1
The POLE c.4198T>C variant is predicted to result in the amino acid substitution p.Tyr1400His. This variant was reported in an individual with familial cancer syndrome (Bhai et al 2021. PubMed ID: 34326862, Table S4). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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.Y1400H variant (also known as c.4198T>C), located in coding exon 33 of the POLE gene, results from a T to C substitution at nucleotide position 4198. The tyrosine at codon 1400 is replaced by histidine, 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at