12-132624979-G-C

Position:

• chr12-132624979-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000320574.10(POLE):​c.6673C>G​(p.Arg2225Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,444 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2225H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: POLE ENST00000320574.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.742

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048003256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.6673C>G	p.Arg2225Gly	missense_variant	48/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4			downstream_gene_variant			XP_011533097.1
POLE	XM_011534797.4			downstream_gene_variant			XP_011533099.1
POLE	XM_011534802.4			downstream_gene_variant			XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6673C>G	p.Arg2225Gly	missense_variant	48/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250346 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461444 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727056

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: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2023

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2225 of the POLE protein (p.Arg2225Gly). This variant is present in population databases (rs765125852, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 967015). 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 with a negative predictive value of 80%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2022

The p.R2225G variant (also known as c.6673C>G), located in coding exon 48 of the POLE gene, results from a C to G substitution at nucleotide position 6673. The arginine at codon 2225 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.034
Sift	Benign	0.51	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0010	B;.
Vest4		0.21
MutPred		0.35		Gain of catalytic residue at V2227 (P = 0);.;
MVP		0.21
MPC		0.24
ClinPred		0.040	T
GERP RS		0.94
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.23
gMVP		0.24

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: rs765125852; hg19: chr12-133201565;