rs2075784

Positions:

• chr12-132687239-G-A

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.62+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,472,344 control chromosomes in the GnomAD database, including 201,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15762 hom., cov: 31)
  • Exomes 𝑓: 0.53 (185584 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.624

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-132687239-G-A is Benign according to our data. Variant chr12-132687239-G-A is described in ClinVar as [Benign]. Clinvar id is 380208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132687239-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.62+15C>T		intron_variant		ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.62+15C>T		intron_variant		1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66009 AN: 150952 Hom.: 15756 Cov.: 31

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.660

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.448

GnomAD3 exomes AF: 0.479 AC: 45218 AN: 94332 Hom.: 11313 AF XY: 0.486 AC XY: 25752 AN XY: 53040

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.409

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.288

Gnomad SAS exome AF: 0.446

Gnomad FIN exome AF: 0.542

Gnomad NFE exome AF: 0.541

Gnomad OTH exome AF: 0.499

GnomAD4 exome AF: 0.525 AC: 694291 AN: 1321288 Hom.: 185584 Cov.: 29 AF XY: 0.523 AC XY: 341223 AN XY: 652046

Gnomad4 AFR exome AF: 0.245

Gnomad4 AMR exome AF: 0.417

Gnomad4 ASJ exome AF: 0.597

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.538

Gnomad4 NFE exome AF: 0.547

Gnomad4 OTH exome AF: 0.510

GnomAD4 genome AF: 0.437 AC: 66022 AN: 151056 Hom.: 15762 Cov.: 31 AF XY: 0.435 AC XY: 32081 AN XY: 73780

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.607

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.439

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.539

Gnomad4 OTH AF: 0.445

Alfa AF: 0.495 Hom.: 3420

Bravo AF: 0.423

Asia WGS AF: 0.403 AC: 1398 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 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	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 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. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: The POLE c.62+15C>T intronic variant involves the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant along with 5/5 splice site tools predicitng the variant not to have an impact on splicing. This variant was found in 5171/10550 control chromosomes (1292 homozygotes) at a frequency of 0.4901422, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Colorectal cancer, susceptibility to, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 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. -

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	10
DANN	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs2075784; hg19: chr12-133263825;