NM_006231.4:c.1270C>G

Variant names:

• chr12-132673664-G-C
• rs483352909
• NM_006231.4:c.1270C>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_006231.4(POLE):​c.1270C>G​(p.Leu424Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,680 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 6.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 12-132673664-G-C is Pathogenic according to our data. Variant chr12-132673664-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132673664-G-C is described in Lovd as [Pathogenic]. Variant chr12-132673664-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.1270C>G	p.Leu424Val	missense_variant	Exon 13 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.1270C>G	p.Leu424Val	missense_variant	Exon 13 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461680 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Feb 03, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This pathogenic variant is denoted POLE c.1270C>G at the cDNA level, p.Leu424Val (L424V) at the protein level, and results in the change of a Leucine to a Valine (CTC>GTC). POLE Leu424Val has been observed in multiple individuals with either an attenuated polyposis phenotype or a history of early onset colorectal cancer, with de novo occurrence reported in two individuals (Palles 2013, Elsayed 2014, Chubb 2015). Additionally, Spier et al. (2014) found this variant to segregate with polyposis and/or colorectal cancer diagnoses in three families. While functional assays have not specifically interrogated POLE Leu424Val, the equivalent residue has been found to have an important role in exonuclease activity in both bacteriophage and yeast systems (Hogg 2004, Murphy 2006). POLE Leu424Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. POLE Leu424Val occurs at a position that is conserved across species and is located in the Exo IV motif of the Exonuclease Domain (Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic. -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 424 of the POLE protein (p.Leu424Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal adenomas and carcinomas (PMID: 23263490, 24501277, 25370038, 25529843, 27683556). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40046). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L424V pathogenic mutation (also known as c.1270C>G), located in coding exon 13 of the POLE gene, results from a C to G substitution at nucleotide position 1270. The leucine at codon 424 is replaced by valine, an amino acid with highly similar properties. This highly conserved residue is in the active site of the exonuclease domain of the POLE protein, and this alteration is predicted to affect the nuclear activity by distorting the packing of helices involved in the exonuclease active site (Palles C et al. Nat. Genet. 2013 Feb; 45(2):136-44). This mutation has been reported as one of the most commonly identified POLE mutations in familial colorectal cancer and polyposis patients. It has been shown to segregate with disease in multiple unrelated families and has not been reported in over six thousand controls or in population cohorts. In addition it has been reported as a de novo occurrence in two individuals (Spier I et al. Int. J. Cancer. 2015 Jul;137(2):320-31; Palles C et al. Nat. Genet. 2013 Feb; 45(2):136-44. Valle L et al. Hum. Mol. Genet. 2014 Jul; 23(13):3506-12. Elsayed FA et al. Eur. J. Hum. Genet. 2015 Aug; 23(8):1080-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Dec 22, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Moderate, PM1_Supporting, PM2_Supporting, PM6_Supporting, PP1_Strong, PP3, PP4_Strong c.1270C>G, located in exon 13 of the POLE gene, is predicted to result in the substitution of Leu by Val at codon 424, p.(Leu424Val). This variant is located at exonuclease domain and within the DNA binding cleft, and < 6Å from the DNA (PM1_Supporting). 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. The REVEL meta-predictor score for this variant (0.65 > 0.644) suggests a deleterious effect on protein function (PP3). Functional assays performed in yeast, mammalian and cell-free assays showed a reduced exonuclease repair function (PMIDs: 32792570, 30362666, 32938641, 29056344, 36915289) (PS3_Moderate). The variant has been identified de novo in a patient with polyposis (more than 10 adenomas) and CRC (PMID 24501277) (PM6_Supporting). In addition, this variant has been identified in 69 carriers from 16 families, showing cosegregation with POLE-associated clinical features (reviewed in PMID: 37848928; PP1_Strong). Whole Exome Sequencing in 6 tumours from TGCA/COSMIC database carrying this variant showed that at least two of them (endometrial and breast) have >5% of combined contribution of signature SBS10 (PMID: 37848928); the same characteristics were also found in a tumour from a germline carrier (PMID: 34594041) (PP4_Strong). This variant has been reported in the ClinVar database (7x pathogenic) and in the LOVD database (2x pathogenic, 6x likely pathogenic, 1x uncertain significance). Based on currently available information, the variant c.1270C>G should be considered a pathogenic variant. -

Polymerase proofreading-related adenomatous polyposis;C3896578:Familial colorectal cancer type X Pathogenic:1

Jun 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis-gastritis-megaloblastic anemia syndrome Pathogenic:1

May 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLE c.1270C>G (p.Leu424Val) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251340 control chromosomes. c.1270C>G has been reported in the literature in multiple individuals affected with Colorectal Cancer or adenomas (e.g. Palles_2013, Chubb_2015, Elsayed_2015, Hamzaoui_2020), including at least one-de novo occurrence (e.g. Valle_2014), as well a co-segregation with disease in multiple families (e.g. Palles_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence indicating that the variant results in a significantly increased mutation rate as assessed by yeast fluctuation assays (e.g. Castellsague_2018, Hamzaoui_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic or risk factor. Based on the evidence outlined above, the variant was classified as pathogenic. -

Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 12 Other:1

Aug 01, 2015

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.76		Gain of catalytic residue at N423 (P = 0);.;
MVP		0.77
MPC		0.78
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.70
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs483352909; hg19: chr12-133250250; COSMIC: COSV57673603; COSMIC: COSV57673603;