12-132676598-G-C

Variant names:

• chr12-132676598-G-C
• rs1057519943
• NM_006231.4:c.857C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006231.4(POLE):​c.857C>G​(p.Pro286Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P286L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 9.95
• Publications: 54 publications found

Genes affected

POLE (HGNC:9177): (DNA polymerase epsilon, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

POLE Gene-Disease associations (from GenCC):

• POLE-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 12

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

  Inheritance: AR Classification: STRONG Submitted by: G2P
• IMAGe syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 12-132676598-G-C is Pathogenic according to our data. Variant chr12-132676598-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376500.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.857C>G	p.Pro286Arg	missense_variant	Exon 9 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.857C>G	p.Pro286Arg	missense_variant	Exon 9 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Endometrioid adenocarcinoma Pathogenic:1

Gynecological Pathology Laboratory, Kaohsiung Medical University Chung-Ho Memorial Hospital

Significance: Established risk allele

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 05, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2_Supporting, PP4_Strong, PS3_Supporting c.857C>G is located in exon 9 of the POLE gene, is predicted to result in the substitution of proline by arginine at codon 286, p.(Pro286Arg). This variant is located at exonuclease domain in a mutation hotspot (PM1). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.837) suggests a deleterious effect on protein function. Whole Exome Sequencing in multiple tumours (MSI and MSS) from TGCA/COSMIC database carrying this variant showed that all of them are hyper or ultramutated and have >50% of combined contribution of signature SBS10 and SBS14 (PMID: 32792570)(PP4_Strong). Functional assays performed in cell lines showed a reduced exonuclease repair function (PMID: 25228659) (PS3_Supporting).In addition, this variant has been reported in the ClinVar (1x uncertain significance, 1x risk allele, 1x drug response)) and in the LOVD database (1x pathogenic). Based on currently available information, the variant c.857C>G is classified as a likely pathogenic variant according to POLE/POLD1 Guidelines (PMID 37848928).

not provided Uncertain:1

Jan 12, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a rare missense change that is not present in the population and has been shown to affect protein function. Although this variant has been found as a frequent somatic event in tumors, it has not been observed in the germline of affected individuals. In the absence of genetic and/or additional evidence, this variant has been classified as Variant of Uncertain Significance. This variant is located within the evolutionarily conserved exonuclease domain of the POLE protein (PMID: 23447401, 24525744). Experimental studies have shown that the P301R yeast mutant, corresponding to the p.Pro286Arg change, severely affects the fidelity rather than the proofreading function of the POLE protein, causing a strong mutator phenotype in a yeast model system (PMID: 24525744). In addition, this variant showed a reduced 3'-5' exonuclease activity compared to the wild-type protein (PMID: 25228659). This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in the germline of individuals with a POLE-related disease, however, it has been reported as a frequent somatic change in endometrial and colorectal cancers (PMID: 23263490, 23447401, 25224212, 24525744). This sequence change replaces proline with arginine at codon 286 of the POLE protein (p.Pro286Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine.

Programmed death ligand-1 (PD-L1) blocking antibody response Other:1

Nov 27, 2017

Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: clinical testing

Association with hypermutated phenotype, likely to respond to anti-PDL1 therapies.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.0083	T
MutationAssessor	Pathogenic	3.3	M;.
PhyloP100		10
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.93
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.87
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057519943; hg19: chr12-133253184; COSMIC: COSV57673247; COSMIC: COSV57673247;