chr12-132632300-C-T

Variant names:

• chr12-132632300-C-T
• rs5745023
• NM_006231.4:c.6330+15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006231.4(POLE):​c.6330+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,601,652 control chromosomes in the GnomAD database, including 170,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19553 hom., cov: 32)
  • Exomes 𝑓: 0.45 (151158 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.184
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• POLE-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 12

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

  Inheritance: AR Classification: STRONG Submitted by: G2P
• IMAGe syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-132632300-C-T is Benign according to our data. Variant chr12-132632300-C-T is described in ClinVar as [Benign]. Clinvar id is 380218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.6330+15G>A		intron_variant	Intron 45 of 48	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.6330+15G>A		intron_variant	Intron 45 of 47		XP_011533097.1
POLE	XM_011534797.4	c.5409+15G>A		intron_variant	Intron 37 of 39		XP_011533099.1
POLE	XM_011534802.4	c.3318+15G>A		intron_variant	Intron 21 of 23		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.6330+15G>A		intron_variant	Intron 45 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75845 AN: 151806 Hom.: 19538 Cov.: 32

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.500

GnomAD2 exomes AF: 0.494 AC: 122871 AN: 248930 AF XY: 0.489

Gnomad AFR exome AF: 0.584

Gnomad AMR exome AF: 0.571

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.704

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.430

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.452 AC: 654914 AN: 1449730 Hom.: 151158 Cov.: 30 AF XY: 0.454 AC XY: 327967 AN XY: 721740

African (AFR) AF: 0.582 AC: 19356 AN: 33246

American (AMR) AF: 0.565 AC: 25183 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 10098 AN: 26042

East Asian (EAS) AF: 0.697 AC: 27627 AN: 39634

South Asian (SAS) AF: 0.546 AC: 46916 AN: 85990

European-Finnish (FIN) AF: 0.427 AC: 22785 AN: 53368

Middle Eastern (MID) AF: 0.501 AC: 2827 AN: 5648

European-Non Finnish (NFE) AF: 0.429 AC: 472550 AN: 1101332

Other (OTH) AF: 0.460 AC: 27572 AN: 59904

GnomAD4 genome AF: 0.500 AC: 75892 AN: 151922 Hom.: 19553 Cov.: 32 AF XY: 0.502 AC XY: 37291 AN XY: 74268

African (AFR) AF: 0.590 AC: 24446 AN: 41408

American (AMR) AF: 0.543 AC: 8295 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1323 AN: 3468

East Asian (EAS) AF: 0.701 AC: 3614 AN: 5156

South Asian (SAS) AF: 0.558 AC: 2686 AN: 4814

European-Finnish (FIN) AF: 0.433 AC: 4567 AN: 10538

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29466 AN: 67958

Other (OTH) AF: 0.502 AC: 1056 AN: 2102

Alfa AF: 0.456 Hom.: 3077

Bravo AF: 0.510

Asia WGS AF: 0.578 AC: 2008 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 30, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 03, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:4

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 19, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: c.6330+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 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 49% (58808/119032 chrs tested), including numerous homozygous occurrences. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.0014%, suggesting that it is a benign polymorphism. 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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 12 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLE-related polyposis and colorectal cancer syndrome Benign:1

Jul 13, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Facial dysmorphism-immunodeficiency-livedo-short stature syndrome Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.59
DANN	Benign	0.47
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5745023; hg19: chr12-133208886;