rs749132017

Positions:

• chr12-132632717-C-G
• chr12-132632717-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_006231.4(POLE):​c.6083G>C​(p.Arg2028Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.31

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3837578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.6083G>C	p.Arg2028Thr	missense_variant	44/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6083G>C	p.Arg2028Thr	missense_variant	44/48		XP_011533097.1
POLE	XM_011534797.4	c.5162G>C	p.Arg1721Thr	missense_variant	36/40		XP_011533099.1
POLE	XM_011534802.4	c.3071G>C	p.Arg1024Thr	missense_variant	20/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6083G>C	p.Arg2028Thr	missense_variant	44/49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249776 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135438

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461568 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727098

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 04, 2023	This variant is present in population databases (rs749132017, gnomAD 0.002%). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 540819). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 2028 of the POLE protein (p.Arg2028Thr). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2022

The p.R2028T variant (also known as c.6083G>C), located in coding exon 44 of the POLE gene, results from a G to C substitution at nucleotide position 6083. The arginine at codon 2028 is replaced by threonine, an amino acid with similar 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	0.13
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.073	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.18
Sift	Benign	0.24	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.078	B;.
Vest4		0.57
MutPred		0.38		Gain of catalytic residue at R2026 (P = 0.0208);.;
MVP		0.57
MPC		0.30
ClinPred		0.21	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.085
gMVP		0.50

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: rs749132017; hg19: chr12-133209303;