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Gene POLE
Variant P286R
Impact List missense
Protein Effect loss of function
Gene Variant Descriptions POLE P286R lies within the exonuclease domain of the Pole protein (PMID: 29352080). P286R is associated with hypermutation in patient samples (PMID: 27612425, PMID: 23528559), results in a perturbation of the DNA-binding pocket by structural modeling (PMID: 23528559), and confers impaired exonuclease activity and increased mutation rate compared to wild-type Pole in vitro (PMID: 25228659, PMID: 29352080).
Associated Drug Resistance
Category Variants Paths

POLE mutant POLE inact mut POLE P286R

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Transcript NM_006231.4
gDNA chr12:g.132676598G>C
cDNA c.857C>G
Protein p.P286R
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_006231.4 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38
XM_011534799.2 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38
XM_047429018.1 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38
NM_006231.3 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38
XM_011534795.4 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38
NM_006231 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38
XM_011534800 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38
XM_011534799 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38
XM_011534795 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38
XM_011534799.3 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38
XM_011534795.3 chr12:g.132676598G>C c.857C>G p.P286R RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
POLE P286R colorectal cancer predicted - sensitive Nivolumab Case Reports/Case Series Actionable In a Phase II trial, Opdivo (nivolumab) resulted in a complete response in a colorectal cancer patient harboring POLE P286R, along with high tumor mutational burden and CD8-positive high tumor infiltrating lymphocytes, and a partial response in a different colorectal cancer patient also harboring POLE P286R, along with high tumor mutational burden (PMID: 35398880; NCT03012581). 35398880
POLE P286R colorectal cancer predicted - sensitive Nivolumab 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 P286R treated with Opdivo (nivolumab) (PMID: 38777726). 38777726
POLE P286R endometrial cancer predicted - sensitive Nivolumab Case Reports/Case Series Actionable In a Phase II trial, Opdivo (nivolumab) resulted in stable disease in an endometrial cancer patient harboring POLE P286R, along with high tumor mutational burden (PMID: 35398880; NCT03012581). 35398880
POLE P286R melanoma sensitive unspecified CTLA4 antibody Preclinical Actionable In a preclinical study, a murine anti-CTLA4 antibody inhibited tumor growth and improved survival in a syngeneic mouse model of melanoma expressing POLE P286R (PMID: 35817971). 35817971
POLE P286R melanoma sensitive unspecified PD-1 antibody Preclinical Actionable In a preclinical study, a murine anti-PD1 antibody inhibited tumor growth and improved survival in a syngeneic mouse model of melanoma expressing POLE P286R (PMID: 35817971). 35817971
POLE P286R melanoma sensitive unspecified CTLA4 antibody + unspecified PD-1 antibody Preclinical Actionable In a preclinical study, the combination of a murine anti-CTLA4 antibody and a murine anti-PD1 antibody inhibited tumor growth and improved survival in a syngeneic mouse model of melanoma expressing POLE P286R (PMID: 35817971). 35817971
POLE P286R colorectal cancer sensitive unspecified CTLA4 antibody Preclinical Actionable In a preclinical study, a murine anti-CTLA4 antibody inhibited tumor growth in a syngeneic mouse model of colorectal cancer expressing POLE P286R (PMID: 35817971). 35817971
POLE P286R colorectal cancer sensitive unspecified PD-1 antibody Preclinical Actionable In a preclinical study, a murine anti-PD1 antibody inhibited tumor growth in a syngeneic mouse model of colorectal cancer expressing POLE P286R (PMID: 35817971). 35817971
POLE P286R colorectal cancer sensitive unspecified CTLA4 antibody + unspecified PD-1 antibody Preclinical Actionable In a preclinical study, the combination of a murine anti-CTLA4 antibody and a murine anti-PD1 antibody inhibited tumor growth in a syngeneic mouse model of colorectal cancer expressing POLE P286R (PMID: 35817971). 35817971
POLE P286R colorectal cancer predicted - sensitive Ipilimumab + Nivolumab 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 partial response in 4 patients and a complete response in 1 patient, all harboring POLE P286R and treated with Yervoy (ipilimumab) plus Opdivo (nivolumab) (PMID: 38777726). 38777726
POLE P286R colorectal cancer predicted - sensitive Pembrolizumab 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 partial response in 2 patients and complete response in 2 patients out of 5 patients harboring POLE P286R and treated with Keytruda (pembrolizumab) (PMID: 38777726). 38777726