12-132626245-C-A

Position:

• chr12-132626245-C-A

Variant summary

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

The ENST00000320574.10(POLE):​c.6403G>T​(p.Val2135Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V2135V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLE ENST00000320574.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

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, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.6403G>T	p.Val2135Phe	missense_variant	46/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6403G>T	p.Val2135Phe	missense_variant	46/48		XP_011533097.1
POLE	XM_011534797.4	c.5482G>T	p.Val1828Phe	missense_variant	38/40		XP_011533099.1
POLE	XM_011534802.4	c.3391G>T	p.Val1131Phe	missense_variant	22/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6403G>T	p.Val2135Phe	missense_variant	46/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 240593). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2135 of the POLE protein (p.Val2135Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;.
Vest4		0.79
MutPred		0.58		Gain of catalytic residue at E2137 (P = 0.0458);.;
MVP		0.60
MPC		0.85
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.65
gMVP		0.80

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: rs878854891; hg19: chr12-133202831;