chr12-132638126-A-G

Position:

• chr12-132638126-A-G

Variant summary

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

The NM_006231.4(POLE):​c.5566T>C​(p.Phe1856Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,344 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: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.22

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.5566T>C	p.Phe1856Leu	missense_variant	41/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5566T>C	p.Phe1856Leu	missense_variant	41/48		XP_011533097.1
POLE	XM_011534797.4	c.4645T>C	p.Phe1549Leu	missense_variant	33/40		XP_011533099.1
POLE	XM_011534802.4	c.2554T>C	p.Phe852Leu	missense_variant	17/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5566T>C	p.Phe1856Leu	missense_variant	41/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151688 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000728

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461656 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727148

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151688 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74026

Gnomad4 AFR AF: 0.0000728

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

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	May 30, 2023	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. 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. ClinVar contains an entry for this variant (Variation ID: 405785). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1856 of the POLE protein (p.Phe1856Leu). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The p.F1856L variant (also known as c.5566T>C), located in coding exon 41 of the POLE gene, results from a T to C substitution at nucleotide position 5566. The phenylalanine at codon 1856 is replaced by leucine, an amino acid with highly similar 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	0.87
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.48
Sift	Benign	0.25	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.034	B;.
Vest4		0.79
MutPred		0.77		Gain of catalytic residue at G1860 (P = 0.0339);.;
MVP		0.34
MPC		0.34
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.48
gMVP		0.56

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: rs1060500846; hg19: chr12-133214712;