12-132626209-G-T

Variant names:

• chr12-132626209-G-T
• NM_006231.4:c.6439C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006231.4(POLE):​c.6439C>A​(p.Pro2147Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.66

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.6439C>A	p.Pro2147Thr	missense_variant	Exon 46 of 49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6439C>A	p.Pro2147Thr	missense_variant	Exon 46 of 48		XP_011533097.1
POLE	XM_011534797.4	c.5518C>A	p.Pro1840Thr	missense_variant	Exon 38 of 40		XP_011533099.1
POLE	XM_011534802.4	c.3427C>A	p.Pro1143Thr	missense_variant	Exon 22 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6439C>A	p.Pro2147Thr	missense_variant	Exon 46 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Aug 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 2447930). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2147 of the POLE protein (p.Pro2147Thr). -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P2147T variant (also known as c.6439C>A), located in coding exon 46 of the POLE gene, results from a C to A substitution at nucleotide position 6439. The proline at codon 2147 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Uncertain	0.54
Sift	Benign	0.041	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		0.94	P;.
Vest4		0.93
MutPred		0.58		Gain of phosphorylation at P2147 (P = 0.0429);.;
MVP		0.73
MPC		0.47
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.54
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-133202795;