rs368662693
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7
The NM_006231.4(POLE):c.6135C>T(p.Pro2045=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P2045P) has been classified as Uncertain significance.
Frequency
Consequence
NM_006231.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.6135C>T | p.Pro2045= | splice_region_variant, synonymous_variant | 44/49 | ENST00000320574.10 | |
POLE | XM_011534795.4 | c.6135C>T | p.Pro2045= | splice_region_variant, synonymous_variant | 44/48 | ||
POLE | XM_011534797.4 | c.5214C>T | p.Pro1738= | splice_region_variant, synonymous_variant | 36/40 | ||
POLE | XM_011534802.4 | c.3123C>T | p.Pro1041= | splice_region_variant, synonymous_variant | 20/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.6135C>T | p.Pro2045= | splice_region_variant, synonymous_variant | 44/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000838 AC: 21AN: 250618Hom.: 0 AF XY: 0.0000811 AC XY: 11AN XY: 135648
GnomAD4 exome AF: 0.0000588 AC: 86AN: 1461694Hom.: 0 Cov.: 32 AF XY: 0.0000536 AC XY: 39AN XY: 727134
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74334
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 18, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Pro2045Pro va riant in POLE has not been previously reported in individuals with colorectal ca ncer but has been identified in 5/8596 of East Asian chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368662693). This variant is located in the last three bases of the exon, which is part of th e 5? splice region. Computational tools do not suggest an impact to splicing. Ho wever, this information is not predictive enough to rule out pathogenicity. In s ummary, the clinical significance of the p.Pro2045Pro variant is uncertain altho ugh it is suspected to be more likely benign. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 29, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2016 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 10, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at