chr12-132639239-T-A

Variant names:

• chr12-132639239-T-A
• rs752559134
• NM_006231.4:c.5438A>T

Variant summary

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

The NM_006231.4(POLE):​c.5438A>T​(p.Tyr1813Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.97

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.5438A>T	p.Tyr1813Phe	missense_variant	Exon 40 of 49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5438A>T	p.Tyr1813Phe	missense_variant	Exon 40 of 48		XP_011533097.1
POLE	XM_011534797.4	c.4517A>T	p.Tyr1506Phe	missense_variant	Exon 32 of 40		XP_011533099.1
POLE	XM_011534802.4	c.2426A>T	p.Tyr809Phe	missense_variant	Exon 16 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5438A>T	p.Tyr1813Phe	missense_variant	Exon 40 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000306

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 17, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1813 of the POLE protein (p.Tyr1813Phe). 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: 540755). 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) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (internal data). 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

Jan 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y1813F variant (also known as c.5438A>T), located in coding exon 40 of the POLE gene, results from an A to T substitution at nucleotide position 5438. The tyrosine at codon 1813 is replaced by phenylalanine, 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.033	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.029
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.0025	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.32	N;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.29	N;N
REVEL	Benign	0.20
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;.
Vest4		0.61
MutPred		0.56		Gain of catalytic residue at Q1817 (P = 0);.;
MVP		0.34
MPC		0.18
ClinPred		0.65	D
GERP RS		5.6
Varity_R		0.22
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: -6

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

Publications

LitVar

Other links and lift over

dbSNP: rs752559134; hg19: chr12-133215825;