12-132657434-A-G

Position:

• chr12-132657434-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006231.4(POLE):​c.3379-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 1,613,706 control chromosomes in the GnomAD database, including 1,214 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 0.026 (146 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1068 hom.)
• Consequence: POLE NM_006231.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004335
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.264

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=-0.8).
• BP6: Variant 12-132657434-A-G is Benign according to our data. Variant chr12-132657434-A-G is described in ClinVar as [Benign]. Clinvar id is 380222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132657434-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.3379-5T>C		splice_region_variant, splice_polypyrimidine_tract_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.3379-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006231.4	ENSP00000322570	P1

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 4009 AN: 152146 Hom.: 139 Cov.: 32

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0382 AC: 9593 AN: 250962 Hom.: 548 AF XY: 0.0331 AC XY: 4491 AN XY: 135648

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.00686

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00686

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0243

Gnomad OTH exome AF: 0.0323

GnomAD4 exome AF: 0.0267 AC: 38990 AN: 1461442 Hom.: 1068 Cov.: 35 AF XY: 0.0256 AC XY: 18601 AN XY: 726998

Gnomad4 AFR exome AF: 0.00421

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.00685

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00730

Gnomad4 FIN exome AF: 0.0312

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0225

GnomAD4 genome AF: 0.0264 AC: 4025 AN: 152264 Hom.: 146 Cov.: 32 AF XY: 0.0283 AC XY: 2104 AN XY: 74454

Gnomad4 AFR AF: 0.00590

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00830

Gnomad4 FIN AF: 0.0313

Gnomad4 NFE AF: 0.0241

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0224 Hom.: 27

Bravo AF: 0.0301

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0202

EpiControl AF: 0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The POLE c.3379-5T>C variant was not identified in the literature, Cosmic, MutDB, or LOVD 3.0. The variant was identified in dbSNP (ID: rs5744886) as “With Benign allele” and ClinVar (classified benign by GeneDx, Laboratory for Molecular Medicine/Partners HealthCare Personalized Medicine, Invitae, and Ambry Genetics). The variant was also identified in control databases in 10094 (549 homozygous) of 276806 chromosomes at a frequency of 0.04 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 5548 (480 homozygous) of 34370 chromosomes (freq: 0.2), African in 136 of 24016 chromosomes (freq: 0.006), Other in 229 (8 homozygous) of 6464 chromosomes (freq: 0.04), European in 3101 (46 homozygous) of 126470 chromosomes (freq: 0.02), Ashkenazi Jewish in 71 (1 homozygous) of 10144 chromosomes (freq: 0.007), East Asian in 4 of 18868 chromosomes (freq: 0.0002), Finnish in 790 (13 homozygous) of 25700 chromosomes (freq: 0.03), and South Asian in 215 (1 homozygous) of 30774 chromosomes (freq: 0.007). The c.3379-5T>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. Positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; however, 5 of 5 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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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: c.3379-5T>C in POLE gene is an intronic change that involves a non-conserved nucleotide. The variant is present in the control population dataset of ExAC at frequency of 0.0333 (3963/118996 chrs tested), predominantly in individuals of Latin descent (0.17; 1945/11380 chrs tested) including numerous homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0014%, suggesting that it is a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports or cited by reputable databases/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 20, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.6
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.036
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: rs5744886; hg19: chr12-133234020;