rs5744833

chr12-132664477-C-T

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.2469-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,608,352 control chromosomes in the GnomAD database, including 2,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (1041 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (1020 hom.)
• Consequence: POLE NM_006231.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.358

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-132664477-C-T is Benign according to our data. Variant chr12-132664477-C-T is described in ClinVar as [Benign]. Clinvar id is 380223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132664477-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.2469-15G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.2469-15G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9874 AN: 152138 Hom.: 1034 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.0468

GnomAD3 exomes AF: 0.0175 AC: 4391 AN: 250480 Hom.: 478 AF XY: 0.0127 AC XY: 1726 AN XY: 135442

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00702

GnomAD4 exome AF: 0.00697 AC: 10150 AN: 1456096 Hom.: 1020 Cov.: 30 AF XY: 0.00604 AC XY: 4376 AN XY: 724758

Gnomad4 AFR exome AF: 0.234

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.000728

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000418

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000621

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0651 AC: 9914 AN: 152256 Hom.: 1041 Cov.: 32 AF XY: 0.0623 AC XY: 4637 AN XY: 74442

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.0464

Alfa AF: 0.0294 Hom.: 90

Bravo AF: 0.0743

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2016	Variant summary: c.2469-15G>A in POLE gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not have a major effect normal on 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 0.022 (2623/120098 chrs tested), predominantly in individuals of African descent 0.237 (2429/10264 chrs tested), including numerous homozygous occurrences. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.00001%, suggesting that it is a benign polymorphism. 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	Invitae	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

- -

Polymerase proofreading-related adenomatous polyposis Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLE c.2469-15G>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs5744833) as "With Benign allele” and ClinVar (classified as benign by GeneDx and Integrated Genetics/Laboratory Corporation of America). The variant was identified in control databases in 6160 of 276308 chromosomes (636 homozygous) at a frequency of 0.02, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 5539 of 23994 chromosomes (freq: 0.23), Other in 64 of 6450 chromosomes (freq: 0.01), Latino in 406 of 34410 chromosomes (freq: 0.01), European in 134 of 126316 chromosomes (freq: 0.001), Ashkenazi Jewish in 9 of 10138 chromosomes (freq: 0.0008), and South Asian in 8 of 30770 chromosomes (freq: 0.0003); it was not observed in the East Asian or Finnish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.2
Dann	Benign	0.27

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: rs5744833; hg19: chr12-133241063;