NM_006231.4:c.3904C>T

Variant names:

• chr12-132649407-G-A
• rs1555223949
• NM_006231.4:c.3904C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_006231.4(POLE):​c.3904C>T​(p.Leu1302Phe) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1302P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.90
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.100544214).
• BP6: Variant 12-132649407-G-A is Benign according to our data. Variant chr12-132649407-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 473632.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.3904C>T	p.Leu1302Phe	missense_variant	Exon 31 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3904C>T	p.Leu1302Phe	missense_variant	Exon 31 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Mar 26, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a POLE-related disease. This sequence change replaces leucine with phenylalanine at codon 1302 of the POLE protein (p.Leu1302Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. -

Colorectal cancer, susceptibility to, 12 Benign:1

Apr 01, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The POLE variant designated as NM_006231.3:c.3904C>T (p.Leu1302Phe) is classified as likely benign. This variant has not been reported in ExAC (exac.broadinstitute.org). This variant is weakly conserved and it is not located in the exonuclease domain in which pathogenic mutations have been reported (Bellido et al, 2016). Additionally, in one observed family, this variant was inherited from an individual who is over 70 years old and who has had regular colonoscopies without colon polyps or colon cancer. Several other relatives of this individual are also over 70 years old and report no colon polyps or colon cancer, providing further evidence against pathogenicity. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 3% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter POLE function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.22
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		2.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.032
Sift	Benign	0.71	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.047	B;B
Vest4		0.24
MutPred		0.38		Gain of catalytic residue at R1303 (P = 0.018);.;
MVP		0.25
MPC		0.20
ClinPred		0.16	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.17
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1555223949; hg19: chr12-133225993;