12-132632440-T-C

Position:

• chr12-132632440-T-C

Variant summary

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

The ENST00000320574.10(POLE):​c.6205A>G​(p.Lys2069Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. K2069N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE ENST00000320574.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.6205A>G	p.Lys2069Glu	missense_variant	45/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6205A>G	p.Lys2069Glu	missense_variant	45/48		XP_011533097.1
POLE	XM_011534797.4	c.5284A>G	p.Lys1762Glu	missense_variant	37/40		XP_011533099.1
POLE	XM_011534802.4	c.3193A>G	p.Lys1065Glu	missense_variant	21/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6205A>G	p.Lys2069Glu	missense_variant	45/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2023

This variant has not been reported in the literature in individuals affected with POLE-related conditions. 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. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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: 540623). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2069 of the POLE protein (p.Lys2069Glu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.20	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.046	B;.
Vest4		0.84
MutPred		0.41		Loss of MoRF binding (P = 0.0035);.;
MVP		0.35
MPC		0.68
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.39
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555220903; hg19: chr12-133209026;