12-132626269-G-C

Position:

• chr12-132626269-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006231.4(POLE):​c.6379C>G​(p.Arg2127Gly) variant causes a missense change involving the alteration of a non-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: 1.56

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.6379C>G	p.Arg2127Gly	missense_variant	46/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6379C>G	p.Arg2127Gly	missense_variant	46/48		XP_011533097.1
POLE	XM_011534797.4	c.5458C>G	p.Arg1820Gly	missense_variant	38/40		XP_011533099.1
POLE	XM_011534802.4	c.3367C>G	p.Arg1123Gly	missense_variant	22/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6379C>G	p.Arg2127Gly	missense_variant	46/49	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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 17, 2018

This sequence change replaces arginine with glycine at codon 2127 of the POLE protein (p.Arg2127Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLE-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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

Apr 28, 2023

The p.R2127G variant (also known as c.6379C>G), located in coding exon 46 of the POLE gene, results from a C to G substitution at nucleotide position 6379. The arginine at codon 2127 is replaced by glycine, an amino acid with dissimilar 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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.98	D;.
Vest4		0.89
MutPred		0.53		Loss of stability (P = 0.0435);.;
MVP		0.63
MPC		0.72
ClinPred		0.99	D
GERP RS		2.6
Varity_R		0.75
gMVP		0.69

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: rs1057517583; hg19: chr12-133202855;