chr12-132635909-G-A

Position:

• chr12-132635909-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006231.4(POLE):​c.5794C>T​(p.Arg1932Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.210

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1263313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.5794C>T	p.Arg1932Cys	missense_variant	42/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5794C>T	p.Arg1932Cys	missense_variant	42/48		XP_011533097.1
POLE	XM_011534797.4	c.4873C>T	p.Arg1625Cys	missense_variant	34/40		XP_011533099.1
POLE	XM_011534802.4	c.2782C>T	p.Arg928Cys	missense_variant	18/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5794C>T	p.Arg1932Cys	missense_variant	42/49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1461192 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000413 Hom.: 0

Bravo AF: 0.00000756

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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1932 of the POLE protein (p.Arg1932Cys). This variant is not present in population databases (gnomAD no frequency). 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: 246233). 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 with a negative predictive value of 80%. 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	GeneDx	Jul 08, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as germline pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25759019, 31829442) -

POLE-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

The POLE c.5794C>T variant is predicted to result in the amino acid substitution p.Arg1932Cys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/246233/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	10
DANN	Benign	0.91
DEOGEN2	Benign	0.056	T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.074
Sift	Benign	0.053	T;T
Sift4G	Uncertain	0.053	T;T
Polyphen		0.63	P;.
Vest4		0.20
MutPred		0.38		Gain of catalytic residue at K1928 (P = 0.0019);.;
MVP		0.30
MPC		0.26
ClinPred		0.25	T
GERP RS		-3.1
Varity_R		0.061
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs879254168; hg19: chr12-133212495; COSMIC: COSV57678092; COSMIC: COSV57678092;