rs73481453

chr12-132624741-T-Achr12-132624741-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006231.4(POLE):c.6817A>T(p.Thr2273Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000837 in 1,613,164 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2273I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (5 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.67

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00729239).
• BP6: Variant 12-132624741-T-A is Benign according to our data. Variant chr12-132624741-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 240621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132624741-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0042 (639/152076) while in subpopulation AFR AF= 0.0147 (608/41480). AF 95% confidence interval is 0.0137. There are 3 homozygotes in gnomad4. There are 315 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.6817A>T	p.Thr2273Ser	missense_variant	49/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.6817A>T	p.Thr2273Ser	missense_variant	49/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 640 AN: 151958 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00480

GnomAD3 exomes AF: 0.00120 AC: 301 AN: 250960 Hom.: 5 AF XY: 0.00102 AC XY: 139 AN XY: 135720

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000487 AC: 711 AN: 1461088 Hom.: 5 Cov.: 30 AF XY: 0.000400 AC XY: 291 AN XY: 726966

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.00420 AC: 639 AN: 152076 Hom.: 3 Cov.: 33 AF XY: 0.00424 AC XY: 315 AN XY: 74358

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00475

Alfa AF: 0.000717 Hom.: 2

Bravo AF: 0.00505

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00152 AC: 184

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 27, 2018	Variant summary: POLE c.6817A>T (p.Thr2273Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 276634 control chromosomes, predominantly at a frequency of 0.016 within the African subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 1126 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.6817A>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2018	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	Jun 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Colorectal cancer, susceptibility to, 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 05, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 20, 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	Sep 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 04, 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. -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLE p.Thr2273Ser variant was not identified in the literature. The variant was identified in dbSNP (ID: rs73481453) as “With other allele” and ClinVar (classified as benign by Invitae, Ambry Genetics and 4 other submitters; and as likely benign by GeneDx and 1 other submitter). The variant was identified in control databases in 424 (5 homozygous) of 276634 chromosomes at a frequency of 0.002, 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 385 (5 homozygous) of 23998 chromosomes (freq: 0.02), Other in 5 of 6450 chromosomes (freq: 0.0008), Latino in 28 of 34420 chromosomes (freq: 0.0008), European Non-Finnish in 5 of 126184 chromosomes (freq: 0.00004), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, East Asian, or European Finnish populations. The p.Thr2273Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Ser impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.058
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0073	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.15
Sift	Benign	0.10	T;T
Sift4G	Benign	0.063	T;T
Polyphen		0.0010	B;.
Vest4		0.13
MutPred		0.52		Gain of catalytic residue at L2274 (P = 5e-04);.;
MVP		0.33
MPC		0.17
ClinPred		0.043	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.14
gMVP		0.36

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: rs73481453; hg19: chr12-133201327;