chr12-132635996-G-A

Position:

• chr12-132635996-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006231.4(POLE):​c.5707C>T​(p.Leu1903Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,613,292 control chromosomes in the GnomAD database, including 19,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1904 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17895 hom.)
• Consequence: POLE NM_006231.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.271

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-132635996-G-A is Benign according to our data. Variant chr12-132635996-G-A is described in ClinVar as [Benign]. Clinvar id is 380216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132635996-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.271 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLE	NM_006231.4	c.5707C>T	p.Leu1903Leu	synonymous_variant	42/49	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5707C>T	p.Leu1903Leu	synonymous_variant	42/48		XP_011533097.1
POLE	XM_011534797.4	c.4786C>T	p.Leu1596Leu	synonymous_variant	34/40		XP_011533099.1
POLE	XM_011534802.4	c.2695C>T	p.Leu899Leu	synonymous_variant	18/24		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5707C>T	p.Leu1903Leu	synonymous_variant	42/49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23269 AN: 152128 Hom.: 1895 Cov.: 33

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.155 AC: 38817 AN: 250976 Hom.: 3199 AF XY: 0.151 AC XY: 20461 AN XY: 135658

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.154 AC: 225645 AN: 1461046 Hom.: 17895 Cov.: 32 AF XY: 0.152 AC XY: 110677 AN XY: 726824

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.219

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.153 AC: 23296 AN: 152246 Hom.: 1904 Cov.: 33 AF XY: 0.153 AC XY: 11415 AN XY: 74438

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.135

Alfa AF: 0.155 Hom.: 3043

Bravo AF: 0.156

Asia WGS AF: 0.135 AC: 471 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.150

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	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, 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	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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.5707C>T (p.Leu1903Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 18491/120772 control chromosomes (1507 homozygotes) at a frequency of 0.1531067, which is approximately 10779 times 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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.29
DANN	Benign	0.46

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: rs5744990; hg19: chr12-133212582; COSMIC: COSV105207326; COSMIC: COSV105207326;