12-132642885-C-T

Position:

• chr12-132642885-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_006231.4(POLE):​c.4663G>A​(p.Val1555Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V1555V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.94

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31284186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.4663G>A	p.Val1555Ile	missense_variant	36/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.4663G>A	p.Val1555Ile	missense_variant	36/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461532 Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9 AN XY: 727068

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: 0.0000126

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 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; Identified in a patient with unspecified cancer in published literature (PMID: 28873162); This variant is associated with the following publications: (PMID: 28873162) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1555 of the POLE protein (p.Val1555Ile). 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: 405661). 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. -

POLE-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2023

The POLE c.4663G>A variant is predicted to result in the amino acid substitution p.Val1555Ile. 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. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2023

The p.V1555I variant (also known as c.4663G>A), located in coding exon 36 of the POLE gene, results from a G to A substitution at nucleotide position 4663. The valine at codon 1555 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Benign	0.088
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.72	N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.16
Sift	Benign	0.15	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.55	P;.
Vest4		0.34
MutPred		0.80		Gain of catalytic residue at E1554 (P = 0.0055);.;
MVP		0.25
MPC		0.18
ClinPred		0.47	T
GERP RS		5.8
Varity_R		0.066
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1060500799; hg19: chr12-133219471;