rs5745075

Positions:

• chr12-132625629-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.6657+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,611,794 control chromosomes in the GnomAD database, including 91,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10024 hom., cov: 33)
  • Exomes 𝑓: 0.33 (81770 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.52

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=-0.87).
• BP6: Variant 12-132625629-G-A is Benign according to our data. Variant chr12-132625629-G-A is described in ClinVar as [Benign]. Clinvar id is 371835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132625629-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.6657+16C>T		intron_variant		ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6657+16C>T		intron_variant			XP_011533097.1
POLE	XM_011534797.4	c.5736+16C>T		intron_variant			XP_011533099.1
POLE	XM_011534802.4	c.3645+16C>T		intron_variant			XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6657+16C>T		intron_variant		1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53617 AN: 151992 Hom.: 10011 Cov.: 33

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.342

GnomAD3 exomes AF: 0.376 AC: 94000 AN: 249782 Hom.: 19475 AF XY: 0.368 AC XY: 49750 AN XY: 135088

Gnomad AFR exome AF: 0.365

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.696

Gnomad SAS exome AF: 0.368

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.334

GnomAD4 exome AF: 0.325 AC: 475107 AN: 1459684 Hom.: 81770 Cov.: 36 AF XY: 0.327 AC XY: 237143 AN XY: 726222

Gnomad4 AFR exome AF: 0.360

Gnomad4 AMR exome AF: 0.476

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.693

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.391

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.324

GnomAD4 genome AF: 0.353 AC: 53646 AN: 152110 Hom.: 10024 Cov.: 33 AF XY: 0.360 AC XY: 26786 AN XY: 74348

Gnomad4 AFR AF: 0.365

Gnomad4 AMR AF: 0.412

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.693

Gnomad4 SAS AF: 0.374

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.344

Alfa AF: 0.314 Hom.: 1438

Bravo AF: 0.356

Asia WGS AF: 0.469 AC: 1626 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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.6657+16C>T variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant, and 5/5 Alamut algorithms predict no significant change to splicing. This variant was found in 44723/120770 control chromosomes (9098 homozygotes) at a frequency of 0.3703155, which is approximately 26070 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), highly suggesting this variant is 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Colorectal cancer, susceptibility to, 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 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

- -

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	-0.87
CADD	Benign	0.15
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs5745075; hg19: chr12-133202215; COSMIC: COSV57683709; COSMIC: COSV57683709;