12-132635899-C-T

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.5804G>A(p.Cys1935Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,612,298 control chromosomes in the GnomAD database, including 30 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1935R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0084 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (15 hom.)
• Consequence: POLE NM_006231.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.426

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=0.0021739304).
• BP6: Variant 12-132635899-C-T is Benign according to our data. Variant chr12-132635899-C-T is described in ClinVar as [Benign]. Clinvar id is 221083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-132635899-C-T is described in Lovd as [Likely_benign]. Variant chr12-132635899-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00837 (1275/152328) while in subpopulation AFR AF= 0.0274 (1140/41568). AF 95% confidence interval is 0.0261. There are 15 homozygotes in gnomad4. There are 604 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.5804G>A	p.Cys1935Tyr	missense_variant	42/49	ENST00000320574.10
POLE	XM_011534795.4	c.5804G>A	p.Cys1935Tyr	missense_variant	42/48
POLE	XM_011534797.4	c.4883G>A	p.Cys1628Tyr	missense_variant	34/40
POLE	XM_011534802.4	c.2792G>A	p.Cys931Tyr	missense_variant	18/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.5804G>A	p.Cys1935Tyr	missense_variant	42/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1277 AN: 152210 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00262 AC: 656 AN: 250074 Hom.: 7 AF XY: 0.00207 AC XY: 280 AN XY: 135200

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00788

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00102 AC: 1489 AN: 1459970 Hom.: 15 Cov.: 31 AF XY: 0.000907 AC XY: 659 AN XY: 726186

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.00829

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000153

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00837 AC: 1275 AN: 152328 Hom.: 15 Cov.: 33 AF XY: 0.00811 AC XY: 604 AN XY: 74488

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00211 Hom.: 5

Bravo AF: 0.0103

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00295 AC: 358

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 12, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 15, 2017	Variant summary: The POLE c.5804G>A (p.Cys1935Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant was found in the control population dataset of ExAC in 358/119342 control chromosomes at a frequency of 0.0029998, which is approximately 211 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. 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. -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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	Jun 07, 2016	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 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	Jan 03, 2018	- -

Polymerase proofreading-related adenomatous polyposis Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLE p.Cys1935Tyr variant was not identified in the literature nor was it identified in the databases. The variant was also identified in dbSNP (ID: rs5744991) as “With Benign allele” and ClinVar (classified benign by Invitae, Counsyl, GeneDx, Ambry Genetics, Quest Diagnostics, Prevention Genetics and True Health Diagnostics). The variant was identified in control databases in 885 of 275994 chromosomes (10 homozygous) at a frequency of 0.003, 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 679 of 24006 chromosomes (10 homozygous, freq: 0.03), Other in 24 of 6428 chromosomes (freq: 0.004), Latino in 74 of 34130 chromosomes (freq: 0.002), European in 29 of 126200 chromosomes (freq: 0.0002), and Ashkenazi Jewish in 79 of 10094 chromosomes (freq: 0.008), while not observed in the East Asian, Finnish, or South Asian populations. The p.Cys1935 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Tyr variant impacts the protein; however, this information is not predictive enough to rule out 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, 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	0.064
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	1.6
Dann	Benign	0.27
DEOGEN2	Benign	0.064	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.33	N;.
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.038
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.097
MVP		0.085
MPC		0.32
ClinPred		0.0017	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.027
gMVP		0.31

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: rs5744991; hg19: chr12-133212485;