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Gene | POLE |
Variant | S459F |
Impact List | missense |
Protein Effect | loss of function |
Gene Variant Descriptions | POLE S459F lies within the exonuclease domain of the Pole protein (PMID: 29352080). S459F results in loss of exonuclease activity in human cells (PMID: 25228659) and increased mutation rates in yeast assays compared to wild-type Pole (PMID: 29352080). |
Associated Drug Resistance | |
Category Variants Paths |
POLE mutant POLE inact mut POLE S459F |
Transcript | NM_006231.4 |
gDNA | chr12:g.132673261G>A |
cDNA | c.1376C>T |
Protein | p.S459F |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
XM_047429018.1 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
XM_011534795 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
XM_011534795.3 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
XM_011534799.3 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
XM_011534800 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
XM_011534795.4 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
NM_006231.3 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
XM_011534799 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
NM_006231.4 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
NM_006231 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
XM_011534799.2 | chr12:g.132673261G>A | c.1376C>T | p.S459F | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
POLE S459F | colorectal cancer | predicted - sensitive | Nivolumab | Case Reports/Case Series | Actionable | In a Phase II trial, Opdivo (nivolumab) resulted in a durable partial response in a colorectal cancer patient harboring POLE S459F, along with high tumor mutational burden (PMID: 35398880; NCT03012581). | 35398880 |
POLE S459F | colorectal cancer | predicted - sensitive | Durvalumab | Case Reports/Case Series | Actionable | In a retrospective study, treatment with immune checkpoint inhibitors resulted in an overall response rate of 89% (22/29) and a disease control rate of 92% in metastatic colorectal cancer patients harboring pathogenic POLE/POLD1 variants, including a complete response in a patient harboring POLE S459F treated with Imfinzi (durvalumab) (PMID: 38777726). | 38777726 |