rs139603739
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_006231.4(POLE):c.3373C>T(p.Arg1125Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000808 in 1,608,584 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1125R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006231.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLE | NM_006231.4 | c.3373C>T | p.Arg1125Ter | stop_gained | 27/49 | ENST00000320574.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLE | ENST00000320574.10 | c.3373C>T | p.Arg1125Ter | stop_gained | 27/49 | 1 | NM_006231.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251436Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135900
GnomAD4 exome AF: 0.00000824 AC: 12AN: 1456368Hom.: 0 Cov.: 29 AF XY: 0.00000966 AC XY: 7AN XY: 724900
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74368
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2016 | This variant is denoted POLE c.3373C>T at the cDNA level and p.Arg1125Ter (R1125X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. While some missense variants in POLE have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), there are no data at this time to support that loss-of-function variants confer the same cancer risks. We therefore consider POLE Arg1125Ter to be a variant of uncertain significance with respect to cancer.To date, the majority of publications regarding POLE and colorectal cancer risk are confined to missense variants within the exonuclease domain (Palles 2013, Spier 2015). However, a splice variant and a frameshift variant have been reported. Pachlopnik Schmid et al. (2012) observed a splice variant at the +3 position in intron 34, in the homozygous state, in 11 family members with facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) from a large consanguineous family; however, they noted that all heterozygous carriers were asymptomatic and did not have a history of cancer. While Smith et al. (2013) identified a POLE frameshift variant in a 26 year old with a history of colorectal cancer, no family history was provided and segregation analysis was not completed. As described above, facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) appears to be a rare autosomal recessive condition associated with two loss-of-function variants in POLE (Pachlopnik Schmid 2012). For individuals and family members of reproductive age, assessment of the reproductive risk associated with being a carrier of a loss of function POLE variant may be considered. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 28, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 16, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 421197). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is present in population databases (rs139603739, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg1125*) in the POLE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 29, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2017 | The p.R1125* variant (also known as c.3373C>T), located in coding exon 27 of the POLE gene, results from a C to T substitution at nucleotide position 3373. This changes the amino acid from an arginine to a stop codon within coding exon 27. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of POLE has not been clearly established as a mechanism of disease. 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