rs5744845

chr12-132661101-G-Achr12-132661101-G-Cchr12-132661101-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006231.4(POLE):c.2928C>T(p.Arg976=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,613,682 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R976R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0090 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (15 hom.)
• Consequence: POLE NM_006231.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.47

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=-0.67).
• BP6: Variant 12-132661101-G-A is Benign according to our data. Variant chr12-132661101-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 240449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132661101-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00901 (1368/151846) while in subpopulation AFR AF= 0.0316 (1306/41332). AF 95% confidence interval is 0.0302. There are 14 homozygotes in gnomad4. There are 646 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.2928C>T	p.Arg976=	synonymous_variant	25/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.2928C>T	p.Arg976=	synonymous_variant	25/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.00902 AC: 1368 AN: 151730 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00578

GnomAD3 exomes AF: 0.00240 AC: 604 AN: 251386 Hom.: 4 AF XY: 0.00170 AC XY: 231 AN XY: 135862

Gnomad AFR exome AF: 0.0320

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000878 AC: 1283 AN: 1461836 Hom.: 15 Cov.: 31 AF XY: 0.000758 AC XY: 551 AN XY: 727224

Gnomad4 AFR exome AF: 0.0311

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00901 AC: 1368 AN: 151846 Hom.: 14 Cov.: 32 AF XY: 0.00871 AC XY: 646 AN XY: 74192

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00572

Alfa AF: 0.00443 Hom.: 1

Bravo AF: 0.00975

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2017	Variant summary: The POLE c.2928C>T (p.Arg976Arg) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 860/251218 control chromosomes at a frequency of 0.0034233, which is approximately 241 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/Likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2017	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	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 16, 2016	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 30, 2015	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. -

Colorectal cancer, susceptibility to, 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	3.9
Dann	Benign	0.83
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

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: rs5744845; hg19: chr12-133237687; COSMIC: COSV57692325; COSMIC: COSV57692325;