12-132667656-C-T

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.2174-8G>A 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 0.014 in 1,613,788 control chromosomes in the GnomAD database, including 188 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (9 hom., cov: 32)
  • Exomes 𝑓: 0.014 (179 hom.)
• Consequence: POLE NM_006231.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001593
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.375

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=-0.77).
• BP6: Variant 12-132667656-C-T is Benign according to our data. Variant chr12-132667656-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132667656-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1687/152308) while in subpopulation NFE AF= 0.0172 (1170/68034). AF 95% confidence interval is 0.0164. There are 9 homozygotes in gnomad4. There are 805 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.2174-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.2174-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1686 AN: 152190 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0220

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0119 AC: 2982 AN: 251098 Hom.: 27 AF XY: 0.0115 AC XY: 1562 AN XY: 135708

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00888

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0143 AC: 20861 AN: 1461480 Hom.: 179 Cov.: 31 AF XY: 0.0138 AC XY: 10059 AN XY: 727060

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00881

Gnomad4 ASJ exome AF: 0.00846

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00336

Gnomad4 FIN exome AF: 0.0197

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0111 AC: 1687 AN: 152308 Hom.: 9 Cov.: 32 AF XY: 0.0108 AC XY: 805 AN XY: 74466

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0220

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.0145 Hom.: 10

Bravo AF: 0.00996

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
Likely 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: ExAC: 1.7% European, intronic -
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, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 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

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2016	Variant summary: c.2174-8G>A in POLE gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.012 (1461/121260 chrs tested), including 4 homozygous occurrences. The observed frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.000014, suggesting that it is a benign polymorphism. The variant of interest has been reported as Benign/Polymorphism by reputable database/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	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 07, 2023	- -

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.2174-8G>A variant was not identified in the literature nor was it identified in the Cosmic and MutDB databases. The variant was identified in dbSNP (ID: rs117409343) as “With other allele”, ClinVar and Clinvitae (5x as benign by Invitae, GeneDx, Quest diagnostics, Laboratory Corporation of America and likely benign by Laboratory for molecular Medicine). The variant was identified in control databases in 3277 of 276912 chromosomes (25 homozygous) at a frequency of 0.012 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 75 of 24034 chromosomes (freq: 0.003), Other in 88 of 6458 chromosomes (freq: 0.013), Latino in 291 of 34418 chromosomes (freq: 0.008), European Non-Finnish in 2146 of 126616 chromosomes (freq: 0.017), Ashkenazi Jewish in 87 of 10152 chromosomes (freq: 0.008), East Asian in 1 of 18870 chromosomes (freq: 0.000053), European Finnish in 502 of 25584 chromosomes (freq: 0.02), and South Asian in 87 of 30780 chromosomes (freq: 0.003). The variant occurs outside of the splicing consensus sequence and 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. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

True Health Diagnostics

Feb 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	2.7
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.080
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: rs117409343; hg19: chr12-133244242;