rs73155056

chr12-132624795-T-Achr12-132624795-T-C

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.6763A>T(p.Ile2255Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,612,582 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. I2255M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0048 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (34 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.266

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=0.002878487).
• BP6: Variant 12-132624795-T-A is Benign according to our data. Variant chr12-132624795-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 221175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132624795-T-A is described in Lovd as [Likely_benign]. Variant chr12-132624795-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00485 (738/152290) while in subpopulation NFE AF= 0.00538 (366/68020). AF 95% confidence interval is 0.00493. There are 6 homozygotes in gnomad4. There are 441 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.6763A>T	p.Ile2255Phe	missense_variant	49/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.6763A>T	p.Ile2255Phe	missense_variant	49/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.00485 AC: 738 AN: 152172 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00538

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00469 AC: 1175 AN: 250552 Hom.: 10 AF XY: 0.00451 AC XY: 611 AN XY: 135526

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0261

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00418 AC: 6100 AN: 1460292 Hom.: 34 Cov.: 29 AF XY: 0.00407 AC XY: 2955 AN XY: 726564

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.00393

Gnomad4 OTH exome AF: 0.00340

GnomAD4 genome AF: 0.00485 AC: 738 AN: 152290 Hom.: 6 Cov.: 33 AF XY: 0.00592 AC XY: 441 AN XY: 74474

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0265

Gnomad4 NFE AF: 0.00538

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00418 Hom.: 1

Bravo AF: 0.00249

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00432 AC: 525

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The POLE p.Ile2255Phe variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs73155056) “With Uncertain significance, other allele” and ClinVar (classified benign by Invitae and Ambry Genetics; and as likely benign by Counsyl, GeneDx, and Quest Diagnostics Nichols Insitute San Juan Capistrano). The variant was identified in control databases in 1455 (13 homozygous) of 276312 chromosomes at a frequency of 0.005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: Finnish in 687 (12 homozygous) of 25786 chromosomes (freq: 0.03), African in 21 of 24016 chromosomes (freq: 0.0009), Other in 40 of 6460 chromosomes (freq: 0.006), Latino in 56 (1 homozygous) of 34420 chromosomes (freq: 0.002), European Non-Finnish in 612 of 125828 chromosomes (freq: 0.005), Ashkenazi Jewish in 22 of 10152 chromosomes (freq: 0.002), and South Asian in 17 of 30782 chromosomes (freq: 0.0006); it was not observed in the East Asian population. The p.Ile2255 residue is conserved in mammals but not in more distantly related organisms. However, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Phe impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 12, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 31, 2017	- -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	POLE: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Colorectal cancer, susceptibility to, 12 Benign:2

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

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 05, 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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 10, 2017	- -

Colorectal cancer, susceptibility to, 12;C3554576:Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;C5193036:Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	17
Dann	Benign	0.95
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.12
Sift	Benign	0.062	T;T
Sift4G	Benign	0.071	T;T
Polyphen		0.022	B;.
Vest4		0.44
MVP		0.24
MPC		0.32
ClinPred		0.010	T
GERP RS		2.5
Varity_R		0.28
gMVP		0.70

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: rs73155056; hg19: chr12-133201381; COSMIC: COSV104629482; COSMIC: COSV104629482;