rs143626223

chr12-132681203-G-Achr12-132681203-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_006231.4(POLE):c.139C>T(p.Arg47Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R47L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:7
• Conservation: PhyloP100: 3.51

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049753696).
• BP6: Variant 12-132681203-G-A is Benign according to our data. Variant chr12-132681203-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240391.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=6, Benign=1}. Variant chr12-132681203-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000808 (123/152234) while in subpopulation NFE AF= 0.00129 (88/68020). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.139C>T	p.Arg47Trp	missense_variant	2/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.139C>T	p.Arg47Trp	missense_variant	2/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000787 AC: 198 AN: 251472 Hom.: 0 AF XY: 0.000868 AC XY: 118 AN XY: 135908

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00105 AC: 1534 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00102 AC XY: 742 AN XY: 727236

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74436

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000684

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000865 AC: 105

EpiCase AF: 0.00147

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	POLE: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2022	The POLE c.139C>T; p.Arg47Trp variant (rs143626223) is reported in the literature in one individual with suspected Lynch syndrome, but without clear disease association (Kayser 2018). This variant is also reported in ClinVar (Variation ID: 240391) and is found in the general population with an overall allele frequency of 0.079% (223/282858 alleles) in the Genome Aggregation Database. The arginine at codon 47 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.132). This variant is not located in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). However, given the lack of clinical and functional data, the significance of the p.Arg47Trp variant is uncertain at this time. References: Kayser et al. Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes. Int J Cancer. 2018 Dec 1;143(11):2800-2813. PMID 29987844. Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. PMID: 23263490. Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516. PMID: 30523343. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	This variant is associated with the following publications: (PMID: 29987844) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 26, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2023	Variant summary: POLE c.139C>T (p.Arg47Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00079 in 251472 control chromosomes (gnomAD), predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. c.139C>T has been reported in the literature in individuals affected hereditary cancers (Kayser_2018, Mur_2020, Guindalini_2022) and inflammatory bowel disease (Biscaglia_2022). These reports do not provide unequivocal conclusions about association of the variant with Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, Genital Anomalies, And Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34347074, 35264596, 29987844, 32792570). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS=8, likely benign=5). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Jul 13, 2018	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 2024	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. -

Colorectal cancer, susceptibility to, 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Jun 22, 2023

The POLE c.139C>T (p.Arg47Trp) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is not located in the exonuclease domain. The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer, inflammatory bowel disease, ovarian cancer, and non-cancer control individuals (PMID: 29641532, 29987844, 31240875, 32546565, 34347074). To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Carcinoma of colon Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLE p.Arg47Trp variant was not identified in the literature nor was it identified in the MutDB, database. The variant was identified in dbSNP (ID: rs143626223) as "With other allele ", ClinVar (classified as likely benign by Invitae, GeneDx; as uncertain significance by Ambry Genetics and two clinical laboratories), and in Cosmic (1x in Genital tract) database. The variant was identified in control databases in 219 of 277204 chromosomes at a frequency of 0.0008 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 4 of 24032 chromosomes (freq: 0.0002), Other in 7 of 6464 chromosomes (freq: 0.001), Latino in 4 of 34420 chromosomes (freq: 0.0001), European in 161 of 126700 chromosomes (freq: 0.001), Finnish in 30 of 25784 chromosomes (freq: 0.001), and South Asian in 13 of 30782 chromosomes (freq: 0.0004), while the variant was not observed in the Ashkenazi Jewish, and East Asian, populations. The p.Arg47 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial colorectal cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Apr 09, 2024

- -

POLE-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;D
Vest4		0.63
MVP		0.56
MPC		0.42
ClinPred		0.080	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.61

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: rs143626223; hg19: chr12-133257789; COSMIC: COSV57675558; COSMIC: COSV57675558;