12-132632393-T-C

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.6252A>G(p.Ser2084=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 1,613,180 control chromosomes in the GnomAD database, including 301,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2084S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.66 (33668 hom., cov: 33)
  • Exomes 𝑓: 0.60 (268244 hom.)
• Consequence: POLE NM_006231.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -4.33

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-132632393-T-C is Benign according to our data. Variant chr12-132632393-T-C is described in ClinVar as [Benign]. Clinvar id is 380217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132632393-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.6252A>G	p.Ser2084=	synonymous_variant	45/49	ENST00000320574.10
POLE	XM_011534795.4	c.6252A>G	p.Ser2084=	synonymous_variant	45/48
POLE	XM_011534797.4	c.5331A>G	p.Ser1777=	synonymous_variant	37/40
POLE	XM_011534802.4	c.3240A>G	p.Ser1080=	synonymous_variant	21/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.6252A>G	p.Ser2084=	synonymous_variant	45/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100172 AN: 151994 Hom.: 33636 Cov.: 33

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.588

Gnomad OTH AF: 0.639

GnomAD3 exomes AF: 0.644 AC: 161809 AN: 251400 Hom.: 53311 AF XY: 0.632 AC XY: 85904 AN XY: 135884

Gnomad AFR exome AF: 0.767

Gnomad AMR exome AF: 0.794

Gnomad ASJ exome AF: 0.531

Gnomad EAS exome AF: 0.813

Gnomad SAS exome AF: 0.613

Gnomad FIN exome AF: 0.577

Gnomad NFE exome AF: 0.585

Gnomad OTH exome AF: 0.627

GnomAD4 exome AF: 0.603 AC: 881194 AN: 1461068 Hom.: 268244 Cov.: 41 AF XY: 0.602 AC XY: 437719 AN XY: 726904

Gnomad4 AFR exome AF: 0.766

Gnomad4 AMR exome AF: 0.784

Gnomad4 ASJ exome AF: 0.532

Gnomad4 EAS exome AF: 0.806

Gnomad4 SAS exome AF: 0.610

Gnomad4 FIN exome AF: 0.574

Gnomad4 NFE exome AF: 0.586

Gnomad4 OTH exome AF: 0.612

GnomAD4 genome AF: 0.659 AC: 100256 AN: 152112 Hom.: 33668 Cov.: 33 AF XY: 0.660 AC XY: 49103 AN XY: 74348

Gnomad4 AFR AF: 0.767

Gnomad4 AMR AF: 0.737

Gnomad4 ASJ AF: 0.526

Gnomad4 EAS AF: 0.803

Gnomad4 SAS AF: 0.626

Gnomad4 FIN AF: 0.579

Gnomad4 NFE AF: 0.588

Gnomad4 OTH AF: 0.641

Alfa AF: 0.603 Hom.: 48177

Bravo AF: 0.675

Asia WGS AF: 0.698 AC: 2425 AN: 3478

EpiCase AF: 0.575

EpiControl AF: 0.575

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 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	PreventionGenetics, part of Exact Sciences	Oct 17, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 17, 2016	Variant summary: The c.6252G>A (p.Ser2084=) in POLE gene is a synonymous 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 0.638 (77431/1211338 chrs tested) including numerous homozygous occurrences. The variant of interest has not, to our knowledge, been reported in affected individuals or cited by reputable databases/clinical laboratories. 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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 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. -

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	-0.91
Cadd	Benign	0.41
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs5745022; hg19: chr12-133208979; COSMIC: COSV105207645; COSMIC: COSV105207645;