rs1064794641

Positions:

• chr12-132641810-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000320574.10(POLE):​c.5215A>G​(p.Ile1739Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,451,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. I1739T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: POLE ENST00000320574.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 2.83

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2242814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.5215A>G	p.Ile1739Val	missense_variant	39/49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5215A>G	p.Ile1739Val	missense_variant	39/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000822 AC: 2 AN: 243162 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132052

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1451466 Hom.: 0 Cov.: 31 AF XY: 0.00000692 AC XY: 5 AN XY: 722382

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 06, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLE protein function. ClinVar contains an entry for this variant (Variation ID: 420695). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1739 of the POLE protein (p.Ile1739Val). -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 09, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2016	This variant is denoted POLE c.5215A>G at the cDNA level, p.Ile1739Val (I1739V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Ile1739Val 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 Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. POLE Ile1739Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLE Ile1739Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Colorectal cancer, susceptibility to, 12 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.5215A>G (p.Ile1739Val) in POLE gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain Significance. The p.Ile1739Val variant is novel (not in any individuals) in 1000 Genomes and is present in the gnomAD exomes database with a frequency of 0.0008%. The amino acid Ile at position 1739 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ile1739Val in POLE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 31, 2022	The POLE c.5215A>G (p.Ile1739Val) missense change has a maximum subpopulation frequency of 0.0029% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with POLE-associated polyposis, FILS syndrome, or IMAGE-I syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.56
DEOGEN2	Benign	0.065	T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	N;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.054
Sift	Benign	0.51	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.0020	B;.
Vest4		0.11
MutPred		0.76		Gain of catalytic residue at N1737 (P = 0.1014);.;
MVP		0.30
MPC		0.16
ClinPred		0.17	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.077
gMVP		0.23

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: rs1064794641; hg19: chr12-133218396;