12-132639149-T-G

Variant names:

• chr12-132639149-T-G
• rs753680242
• NM_006231.4:c.5528A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006231.4(POLE):​c.5528A>C​(p.Asn1843Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. N1843S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.902
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• POLE-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 12

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

  Inheritance: AR Classification: STRONG Submitted by: G2P
• IMAGe syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27762663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.5528A>C	p.Asn1843Thr	missense_variant	Exon 40 of 49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5528A>C	p.Asn1843Thr	missense_variant	Exon 40 of 48		XP_011533097.1
POLE	XM_011534797.4	c.4607A>C	p.Asn1536Thr	missense_variant	Exon 32 of 40		XP_011533099.1
POLE	XM_011534802.4	c.2516A>C	p.Asn839Thr	missense_variant	Exon 16 of 24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5528A>C	p.Asn1843Thr	missense_variant	Exon 40 of 49	1	NM_006231.4	ENSP00000322570.5

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

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N1843T variant (also known as c.5528A>C), located in coding exon 40 of the POLE gene, results from an A to C substitution at nucleotide position 5528. The asparagine at codon 1843 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
PhyloP100		0.90
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.062
Sift	Benign	0.53	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.0020	B;.
Vest4		0.54
MutPred		0.66		Gain of catalytic residue at M1844 (P = 0.0102);.;
MVP		0.31
MPC		0.19
ClinPred		0.11	T
GERP RS		0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.050
gMVP		0.23
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs753680242; hg19: chr12-133215735;