chr12-132642903-G-C
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_006231.4(POLE):c.4645C>G(p.Pro1549Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1549H) has been classified as Uncertain significance.
Frequency
Consequence
NM_006231.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.4645C>G | p.Pro1549Ala | missense_variant | 36/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.4645C>G | p.Pro1549Ala | missense_variant | 36/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000256 AC: 39AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000375 AC: 94AN: 250748Hom.: 0 AF XY: 0.000280 AC XY: 38AN XY: 135562
GnomAD4 exome AF: 0.000192 AC: 280AN: 1461366Hom.: 0 Cov.: 34 AF XY: 0.000171 AC XY: 124AN XY: 726966
GnomAD4 genome ? AF: 0.000256 AC: 39AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.000174 AC XY: 13AN XY: 74502
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 24, 2019 | The POLE c.4645C>G; p.Pro1549Ala variant (rs147500308), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 240531). This variant is found in the general population with an overall allele frequency of 0.04% (101/282144 alleles) in the Genome Aggregation Database. The proline at codon 1549 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to the lack of clinical and functional data, the clinical significance of this variant is uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 28, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 27, 2021 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 22, 2017 | - - |
Colorectal cancer, susceptibility to, 12 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
POLE-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 04, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 26, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at