rs11146986

chr12-132641691-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.5334C>T(p.Ala1778=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,613,910 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (150 hom.)
• Consequence: POLE NM_006231.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.651

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=-0.8).
• BP6: Variant 12-132641691-G-A is Benign according to our data. Variant chr12-132641691-G-A is described in ClinVar as [Benign]. Clinvar id is 380429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132641691-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.651 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.5334C>T	p.Ala1778=	synonymous_variant	39/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.5334C>T	p.Ala1778=	synonymous_variant	39/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152176 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0776

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00614 AC: 1541 AN: 251010 Hom.: 52 AF XY: 0.00586 AC XY: 795 AN XY: 135728

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0764

Gnomad SAS exome AF: 0.00340

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00272 AC: 3969 AN: 1461616 Hom.: 150 Cov.: 31 AF XY: 0.00274 AC XY: 1991 AN XY: 727126

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0851

Gnomad4 SAS exome AF: 0.00334

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000755

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.00297 AC: 453 AN: 152294 Hom.: 11 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74460

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0774

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000461 Hom.: 1

Bravo AF: 0.00356

Asia WGS AF: 0.0200 AC: 72 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 10, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	May 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 02, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 28, 2017	Variant summary: The POLE c.5334C>T (p.Ala1778Ala) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, these predictions have yet to be confirmed by functional studies. This variant was found in 760/120604 control chromosomes (23 homozygotes), predominantly in the East Asian cohort at a frequency of 0.079643 (687/8626). This frequency is about 5607 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in population(s) of East Asian origin. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. -

Colorectal cancer, susceptibility to, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Endometrial carcinoma Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLE p.Ala1778= variant was identified in the literature however the frequency of this variant in an affected population was not provided (Yamaguchi_2016_27217144). The variant was also identified in dbSNP (ID: rs11146986) as “With Benign allele”, ClinVar and Clinvitae (5x as benign by GeneDx, Invitae, Quest Diagnostics, Ambry Genetics, Laboratory Corrporation of America), databases. The variant was not identified in Cosmic and MutDB databases. The variant was identified in control databases in 1594 of 276784 chromosomes (51 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 6 of 24018 chromosomes (freq: 0.00025), “Other” in 13 of 6462 chromosomes (freq: 0.002), Latino in 3 of 34420 chromosomes (freq: 0.000087), European Non-Finnish in 14 of 126618 chromosomes (freq: 0.00011), East Asian in 1453 of 18856 chromosomes (freq: 0.08), and South Asian in 105 of 30778 chromosomes (freq: 0.003412), while the variant was not observed in the Ashkenazi Jewish and European Finnish populations. The p.Ala1778Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.8
Dann	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11146986; hg19: chr12-133218277; COSMIC: COSV100265508; COSMIC: COSV100265508;