chr12-132635876-A-G

Variant names:

• chr12-132635876-A-G
• rs115381003
• NM_006231.4:c.5811+16T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006231.4(POLE):​c.5811+16T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,600,006 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (6 hom.)
• Consequence: POLE NM_006231.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.67

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-132635876-A-G is Benign according to our data. Variant chr12-132635876-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 371907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00389 (592/152354) while in subpopulation AFR AF = 0.0136 (564/41582). AF 95% confidence interval is 0.0126. There are 2 homozygotes in GnomAd4. There are 274 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.5811+16T>C		intron_variant	Intron 42 of 48	ENST00000320574.10	NP_006222.2
POLE	XM_011534795.4	c.5811+16T>C		intron_variant	Intron 42 of 47		XP_011533097.1
POLE	XM_011534797.4	c.4890+16T>C		intron_variant	Intron 34 of 39		XP_011533099.1
POLE	XM_011534802.4	c.2799+16T>C		intron_variant	Intron 18 of 23		XP_011533104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.5811+16T>C		intron_variant	Intron 42 of 48	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 152236 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00101 AC: 246 AN: 244354 AF XY: 0.000643

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.000456

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000415 AC: 601 AN: 1447652 Hom.: 6 Cov.: 31 AF XY: 0.000341 AC XY: 245 AN XY: 718464

African (AFR) AF: 0.0149 AC: 492 AN: 33012

American (AMR) AF: 0.000605 AC: 26 AN: 42980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25576

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39426

South Asian (SAS) AF: 0.00 AC: 0 AN: 85058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53134

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.0000218 AC: 24 AN: 1103024

Other (OTH) AF: 0.000954 AC: 57 AN: 59746

GnomAD4 genome AF: 0.00389 AC: 592 AN: 152354 Hom.: 2 Cov.: 33 AF XY: 0.00368 AC XY: 274 AN XY: 74506

African (AFR) AF: 0.0136 AC: 564 AN: 41582

American (AMR) AF: 0.00124 AC: 19 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00221 Hom.: 1

Bravo AF: 0.00452

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 21, 2017

GeneDx

Significance: Likely 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. -

Dec 11, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, susceptibility to, 12 Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Aug 07, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	-0.85
CADD	Benign	0.024
DANN	Benign	0.54
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs115381003; hg19: chr12-133212462;