12-132639201-G-A

Position:

• chr12-132639201-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_006231.4(POLE):​c.5476C>T​(p.Arg1826Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.58

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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.5476C>T	p.Arg1826Trp	missense_variant	40/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5476C>T	p.Arg1826Trp	missense_variant	40/48		XP_011533097.1
POLE	XM_011534797.4	c.4555C>T	p.Arg1519Trp	missense_variant	32/40		XP_011533099.1
POLE	XM_011534802.4	c.2464C>T	p.Arg822Trp	missense_variant	16/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5476C>T	p.Arg1826Trp	missense_variant	40/49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251436 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 19, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 11, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1826 of the POLE protein (p.Arg1826Trp). This variant is present in population databases (rs762000608, gnomAD 0.01%). 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: 583360). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: variant designated functionally abnormal based on an in vitro assay measuring cell survival (PMID: 34749799); This variant is associated with the following publications: (PMID: 34749799) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.99	D;.
Vest4		0.74
MutPred		0.62		Gain of catalytic residue at R1823 (P = 0.004);.;
MVP		0.57
MPC		0.73
ClinPred		0.85	D
GERP RS		5.6
Varity_R		0.53
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs762000608; hg19: chr12-133215787; COSMIC: COSV57677164; COSMIC: COSV57677164;