12-132638022-G-C

Position:

• chr12-132638022-G-C

Variant summary

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

The ENST00000320574.10(POLE):​c.5670C>G​(p.Ile1890Met) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1890V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE ENST00000320574.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04

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, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.5670C>G	p.Ile1890Met	missense_variant	41/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5670C>G	p.Ile1890Met	missense_variant	41/48		XP_011533097.1
POLE	XM_011534797.4	c.4749C>G	p.Ile1583Met	missense_variant	33/40		XP_011533099.1
POLE	XM_011534802.4	c.2658C>G	p.Ile886Met	missense_variant	17/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5670C>G	p.Ile1890Met	missense_variant	41/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Aug 07, 2018

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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with POLE-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 1890 of the POLE protein (p.Ile1890Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.43	B;.
Vest4		0.63
MutPred		0.66		Gain of catalytic residue at E1888 (P = 0.0021);.;
MVP		0.46
MPC		0.68
ClinPred		0.91	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.57

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: rs1037020157; hg19: chr12-133214608;