rs139075637

Variant names:

• chr12-132676594-A-T
• rs139075637
• NM_006231.4:c.861T>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006231.4(POLE):​c.861T>A​(p.Asp287Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,080 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:10 O:2
• Conservation: PhyloP100: 1.19

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044186294).
• BP6: Variant 12-132676594-A-T is Benign according to our data. Variant chr12-132676594-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221000.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Benign=3, Likely_benign=6, not_provided=2}. Variant chr12-132676594-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00116 (176/152294) while in subpopulation NFE AF= 0.00215 (146/68016). AF 95% confidence interval is 0.00186. There are 1 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.861T>A	p.Asp287Glu	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.861T>A	p.Asp287Glu	missense_variant	Exon 9 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152176 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000859 AC: 216 AN: 251450 Hom.: 0 AF XY: 0.000758 AC XY: 103 AN XY: 135908

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.00137 AC: 1999 AN: 1461786 Hom.: 3 Cov.: 31 AF XY: 0.00130 AC XY: 942 AN XY: 727194

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152294 Hom.: 1 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74472

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00111

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000865 AC: 105

EpiCase AF: 0.00147

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:10 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2025	POLE: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2020	This variant is associated with the following publications: (PMID: 26648449, 30374176, 30680046, 30971823, 30414346, 29454559, 29120461, 29185122, 28873162, 27720647, 27153395, 25224212, 26251183) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Colorectal cancer, susceptibility to, 12 Uncertain:3 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 19, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Aug 13, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2016	- -
Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Mar 28, 2018	The POLE variant designated as NM_006231.2:c.861T>A (p.Asp287Glu) is classified as likely benign. This variant has been reported at a frequency of over 1 in 400 individuals in individuals with European non-Finnish ancestry (exac.broadinstitute.org). Variants present at this population frequency are unlikely to be associated with high penetrance hereditary cancer risk. Cosegregation analysis of one observed family was performed and shows a likelihood ratio of pathogenicity of 0.98 to 1 (Thompson, et al., 2003, PMID:2900794). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter POLE function or modify cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 12-21-2015 by Lab Ambry. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2020	DNA sequence analysis of the POLE gene demonstrated a sequence change, c.861T>A, in exon 9 that results in an amino acid change, p.Asp287Glu. This sequence change has been described in the gnomAD database with a frequency of 0.18% in the European sub-population (dbSNP rs139075637). The p.Asp287Glu change has been reported in one suspected Lynch syndrome patient (PMID: 26648449) and nine melanoma patients (PMID: 30414346). This sequence change has also been reported in three families with cutaneous malignant melanoma; however, incomplete segregation with disease was observed (PMID: 26251183). The p.Asp287Glu change affects a highly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. The p.Asp287Glu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp287Glu change remains unknown at this time. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2018	Variant summary: POLE c.861T>A (p.Asp287Glu) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 277192 control chromosomes, predominantly at a frequency of 0.0017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 120-folds higher then the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.861T>A has been reported in the literature in individuals affected with cutaneous malignant melanoma, endometrial cancer and Lynch Syndrome (Aoude_2015, Billingsley_2015, Jansen_2016, Potjer_2018). Two families published by Auode_2015 indicate the variant did not segregate with disease, along with Jansen_2016 reporting a patient with the variant of interest, who had two MLH1 pathogenic somatic variants, c.208-1G>A and c.440_447del. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) predominantly cite the variant as uncertain significance, while two cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 04, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 01, 2018	- -

Colorectal cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Oct 01, 2016

Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 32 year old male with gastric cancer, bladder cancer and colon polyps. Family history of gastric cancer and colon polyps. Patient also has a pathogenic variant in CDH1. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

POLE-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.65
MutPred		0.37		Gain of catalytic residue at Q292 (P = 0);.;
MVP		0.37
MPC		0.75
ClinPred		0.11	T
GERP RS		1.9
Varity_R		0.53
gMVP		0.62

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: rs139075637; hg19: chr12-133253180; COSMIC: COSV57691380; COSMIC: COSV57691380;