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Gene | POLD1 |
Variant | L606M |
Impact List | missense |
Protein Effect | loss of function - predicted |
Gene Variant Descriptions | POLD1 L606M lies within the polymerase domain of the Pold1 protein (PMID: 27093186). L606M results in increased polymerase activity and exonuclease activity but increased base substitution error rate and mutational rate compared to wild-type Pold1 (PMID: 19540301), and therefore is predicted to lead to a loss of Pold1 protein function. |
Associated Drug Resistance | |
Category Variants Paths |
POLD1 mutant POLD1 inact mut POLD1 L606M |
Transcript | NM_002691.4 |
gDNA | chr19:g.50408825C>A |
cDNA | c.1816C>A |
Protein | p.L606M |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
XM_011527038.2 | chr19:g.50408825C>A | c.1816C>A | p.L606M | RefSeq | GRCh38/hg38 |
XM_047438947.1 | chr19:g.50408825C>A | c.1816C>A | p.L606M | RefSeq | GRCh38/hg38 |
XM_047438949.1 | chr19:g.50408825C>A | c.1816C>A | p.L606M | RefSeq | GRCh38/hg38 |
NM_001256849.1 | chr19:g.50408825C>A | c.1816C>A | p.L606M | RefSeq | GRCh38/hg38 |
XM_005259008.5 | chr19:g.50408825C>A | c.1816C>A | p.L606M | RefSeq | GRCh38/hg38 |
XM_017026882.3 | chr19:g.50408825C>A | c.1816C>A | p.L606M | RefSeq | GRCh38/hg38 |
NM_002691.4 | chr19:g.50408825C>A | c.1816C>A | p.L606M | RefSeq | GRCh38/hg38 |
XM_047438946.1 | chr19:g.50408825C>A | c.1816C>A | p.L606M | RefSeq | GRCh38/hg38 |
XM_047438948.1 | chr19:g.50408825C>A | c.1816C>A | p.L606M | RefSeq | GRCh38/hg38 |
XM_047438950.1 | chr19:g.50408825C>A | c.1816C>A | p.L606M | RefSeq | GRCh38/hg38 |
NM_001308632.1 | chr19:g.50408747_50408749delCTAinsATG | c.1816_1818delCTAinsATG | p.L606M | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
POLD1 inact mut | rectum cancer | sensitive | Nivolumab | Guideline | Actionable | Opdivo (nivolumab) is included in guidelines as systemic therapy for patients with advanced or metastatic rectal cancer harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | small intestine adenocarcinoma | sensitive | Ipilimumab + Nivolumab | Guideline | Actionable | Opdivo (nivolumab) in combination with Yervoy (ipilimumab) is included in guidelines as an initial therapy for patients with advanced or metastatic small bowel adenocarcinoma harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | colon cancer | sensitive | Ipilimumab + Nivolumab | Guideline | Actionable | Opdivo (nivolumab) in combination with Yervoy (ipilimumab) is included in guidelines as systemic therapy for patients with advanced or metastatic colon cancer harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | colon cancer | sensitive | Nivolumab | Guideline | Actionable | Opdivo (nivolumab) is included in guidelines as systemic therapy for patients with advanced or metastatic colon cancer harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | Advanced Solid Tumor | sensitive | E7449 | Preclinical | Actionable | In a preclinical study, E7449 inhibited proliferation of a POLD1-deficient cell line in culture, which demonstrated increased sensitivity compared to cells without DNA repair pathway mutations (PMID: 26513298). | 26513298 |
POLD1 inact mut | small intestine adenocarcinoma | sensitive | Dostarlimab-gxly | Guideline | Actionable | Jemperli (dostarlimab-gxly) is included in guidelines as a subsequent therapy for patients with advanced or metastatic small bowel adenocarcinoma harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | rectum cancer | sensitive | Dostarlimab-gxly | Guideline | Actionable | Jemperli (dostarlimab-gxly) is included in guidelines as subsequent therapy for patients with advanced or metastatic rectal cancer harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | rectum cancer | sensitive | Pembrolizumab | Guideline | Actionable | Keytruda (pembrolizumab) is included in guidelines as systemic therapy for patients with advanced or metastatic rectal cancer harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | rectum cancer | sensitive | Ipilimumab + Nivolumab | Guideline | Actionable | Opdivo (nivolumab) in combination with Yervoy (ipilimumab) is included in guidelines as systemic therapy for patients with advanced or metastatic rectal cancer harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | small intestine adenocarcinoma | sensitive | Pembrolizumab | Guideline | Actionable | Keytruda (pembrolizumab) is included in guidelines as an initial therapy for patients with advanced or metastatic small bowel adenocarcinoma harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | colorectal cancer | not applicable | N/A | Guideline | Prognostic | POLD1 inactivating mutations are associated with a more favorable prognosis in patients with colorectal cancer (NCCN.org). | detail... |
POLD1 inact mut | colon cancer | sensitive | Dostarlimab-gxly | Guideline | Actionable | Jemperli (dostarlimab-gxly) is included in guidelines as subsequent therapy for patients with advanced or metastatic colon cancer harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | colon cancer | sensitive | Pembrolizumab | Guideline | Actionable | Keytruda (pembrolizumab) is included in guidelines as systemic therapy for patients with advanced or metastatic colon cancer harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 inact mut | colorectal carcinoma | not applicable | N/A | Guideline | Risk Factor | Germline POLD1 inactivating mutations result in polymerase proofreading-associated polyposis and are associated with increased risk of developing colorectal carcinoma (NCCN.org). | detail... |
POLD1 inact mut | small intestine adenocarcinoma | sensitive | Nivolumab | Guideline | Actionable | Opdivo (nivolumab) is included in guidelines as an initial therapy for patients with advanced or metastatic small bowel adenocarcinoma harboring POLD1 inactivating mutations (NCCN.org). | detail... |
POLD1 mutant | Advanced Solid Tumor | predicted - sensitive | unspecified PD-1 antibody | Clinical Study - Cohort | Actionable | In a clinical study, immune checkpoint inhibitor (ICI) treatment, including CTLA4, PD-1, and PD-L1-targeting antibodies, resulted in prolonged overall survival (34 vs 18 months, p=0.004) in patients with advanced solid tumors harboring POLE or POLD1 mutations compared to wild-type patients, and POLE/POLD1 mutation served as a predictor of response to ICI (p=0.047, HR=1.41) independent of MSI-H status (PMID: 31415061). | 31415061 |
POLD1 mutant | Advanced Solid Tumor | predicted - sensitive | unspecified PD-L1 antibody | Clinical Study - Cohort | Actionable | In a clinical study, immune checkpoint inhibitor (ICI) treatment, including CTLA4, PD-1, and PD-L1-targeting antibodies, resulted in prolonged overall survival (34 vs 18 months, p=0.004) in patients with advanced solid tumors harboring POLE or POLD1 mutations compared to wild-type patients, and POLE/POLD1 mutation served as a predictor of response to ICI (p=0.047, HR=1.41) independent of MSI-H status (PMID: 31415061). | 31415061 |
POLD1 mutant | Advanced Solid Tumor | predicted - sensitive | unspecified CTLA4 antibody | Clinical Study - Cohort | Actionable | In a clinical study, immune checkpoint inhibitor (ICI) treatment, including CTLA4, PD-1, and PD-L1-targeting antibodies, resulted in prolonged overall survival (34 vs 18 months, p=0.004) in patients with advanced solid tumors harboring POLE or POLD1 mutations compared to wild-type patients, and POLE/POLD1 mutation served as a predictor of response to ICI (p=0.047, HR=1.41) independent of MSI-H status (PMID: 31415061). | 31415061 |