12-132649756-T-A

Position:

• chr12-132649756-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006231.4(POLE):​c.3716A>T​(p.Gln1239Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.72

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30763412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.3716A>T	p.Gln1239Leu	missense_variant	30/49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3716A>T	p.Gln1239Leu	missense_variant	30/49	1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

POLE-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 17, 2023

The POLE c.3716A>T variant is predicted to result in the amino acid substitution p.Gln1239Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/935769/). Alternative variant at this codon (c.3715C>G, p.Gln1239Glu) has been observed in an individual with breast cancer and was assessed as variant of uncertain significance (Table S3, Guindalini et al. 2022. PubMed ID: 35264596). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2019

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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with POLE-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with leucine at codon 1239 of the POLE protein (p.Gln1239Leu). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and leucine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2022

The p.Q1239L variant (also known as c.3716A>T), located in coding exon 30 of the POLE gene, results from an A to T substitution at nucleotide position 3716. The glutamine at codon 1239 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Benign	0.092
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	0.044
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.16
Sift	Benign	0.26	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0010	B;B
Vest4		0.60
MutPred		0.35		Loss of disorder (P = 0.0666);.;
MVP		0.42
MPC		0.18
ClinPred		0.85	D
GERP RS		5.9
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.26
gMVP		0.36

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: rs146210785; hg19: chr12-133226342;