dbSNP rs1060500871: POLE:p.Val2204Leu (chr12-132625692-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006231.4(POLE):c.6610G>T(p.Val2204Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

POLE
NM_006231.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.99

Variant links:

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]

POLE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4 link	c.6610G>T	p.Val2204Leu	missense_variant	Exon 47 of 49	ENST00000320574.10	NP_006222.2	Q07864
POLE	XM_011534795.4 link	c.6610G>T	p.Val2204Leu	missense_variant	Exon 47 of 48		XP_011533097.1
POLE	XM_011534797.4 link	c.5689G>T	p.Val1897Leu	missense_variant	Exon 39 of 40		XP_011533099.1
POLE	XM_011534802.4 link	c.3598G>T	p.Val1200Leu	missense_variant	Exon 23 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10 link	c.6610G>T	p.Val2204Leu	missense_variant	Exon 47 of 49	1	NM_006231.4	ENSP00000322570.5		Q07864

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 405849). 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 leucine, which is neutral and non-polar, at codon 2204 of the POLE protein (p.Val2204Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.064

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.036

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.37

N;N

REVEL

Benign

0.12

Sift

Benign

0.87

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.023

B;.

Vest4

0.60

MutPred

0.57

Gain of catalytic residue at V2204 (P = 0.0258);.;

MVP

0.35

MPC

0.19

ClinPred

0.42

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over