rs5744936

Positions:

• chr12-132643832-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006231.4(POLE):​c.4290+5C>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,612,088 control chromosomes in the GnomAD database, including 528 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (53 hom., cov: 33)
  • Exomes 𝑓: 0.023 (475 hom.)
• Consequence: POLE NM_006231.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.0001190
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.0120

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-132643832-G-A is Benign according to our data. Variant chr12-132643832-G-A is described in ClinVar as [Benign]. Clinvar id is 380226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132643832-G-A is described in Lovd as [Benign]. Variant chr12-132643832-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0207 (3155/152292) while in subpopulation EAS AF= 0.028 (145/5186). AF 95% confidence interval is 0.0265. There are 53 homozygotes in gnomad4. There are 1600 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 53 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.4290+5C>T		splice_donor_5th_base_variant, intron_variant		ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.4290+5C>T		splice_donor_5th_base_variant, intron_variant		1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 3157 AN: 152174 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0236 AC: 5910 AN: 250510 Hom.: 83 AF XY: 0.0241 AC XY: 3270 AN XY: 135426

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.0340

Gnomad SAS exome AF: 0.0245

Gnomad FIN exome AF: 0.0417

Gnomad NFE exome AF: 0.0252

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0233 AC: 34014 AN: 1459796 Hom.: 475 Cov.: 32 AF XY: 0.0236 AC XY: 17126 AN XY: 725830

Gnomad4 AFR exome AF: 0.00356

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0170

Gnomad4 EAS exome AF: 0.0290

Gnomad4 SAS exome AF: 0.0214

Gnomad4 FIN exome AF: 0.0418

Gnomad4 NFE exome AF: 0.0237

Gnomad4 OTH exome AF: 0.0212

GnomAD4 genome AF: 0.0207 AC: 3155 AN: 152292 Hom.: 53 Cov.: 33 AF XY: 0.0215 AC XY: 1600 AN XY: 74464

Gnomad4 AFR AF: 0.00423

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.0280

Gnomad4 SAS AF: 0.0255

Gnomad4 FIN AF: 0.0414

Gnomad4 NFE AF: 0.0275

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0223 Hom.: 34

Bravo AF: 0.0172

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.0231

EpiControl AF: 0.0226

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2016	Variant summary: The POLE c.4290+5C>T variant involves the alteration of a non-conserved nucleotide located in an intronic position outside of the canonical slice sites. Mutation taster predicts a damaging outcome for this variant while 5/5 in silico tools via Alamut predict the variant no to have a significant impact on splicing. The variant was found in 2827/117634 control chromosomes (40 homozygotes) at a frequency of 0.0240322, which is approximately 1692 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 28, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 21, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Colorectal cancer, susceptibility to, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLE c.4290+5C>T variant was not identified in the literature nor was it identified in the Cosmic and MutDB databases. The variant was identified in dbSNP (ID: rs5744936) “With Benign allele”, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (2x), and in control databases in 6696 (102 homozygous) of 276312 chromosomes at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 94 (1 homozygous) of 24002 chromosomes (freq: 0.004), Other in 171 (1 homozygous) of 6448 chromosomes (freq: 0.03), Latino in 414 (2 homozygous) of 34364 chromosomes (freq: 0.01), European Non-Finnish in 3397 (47 homozygous) of 126076 chromosomes (freq: 0.03), Ashkenazi Jewish in 162 (1 homozygous) of 10110 chromosomes (freq: 0.02), East Asian in 626 (12 homozygous) of 18858 chromosomes (freq: 0.03), European Finnish in 1086 (27 homozygous) of 25750 chromosomes (freq: 0.04), and South Asian in 746 (11 homozygous) of 30704 chromosomes (freq: 0.02). The c.4290+5C>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0040
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: rs5744936; hg19: chr12-133220418;