rs368662693

chr12-132632665-G-Achr12-132632665-G-Cchr12-132632665-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_006231.4(POLE):c.6135C>T(p.Pro2045=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P2045P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: POLE NM_006231.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001231
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.268

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 12-132632665-G-A is Benign according to our data. Variant chr12-132632665-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 382254.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.268 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.6135C>T	p.Pro2045=	splice_region_variant, synonymous_variant	44/49	ENST00000320574.10
POLE	XM_011534795.4	c.6135C>T	p.Pro2045=	splice_region_variant, synonymous_variant	44/48
POLE	XM_011534797.4	c.5214C>T	p.Pro1738=	splice_region_variant, synonymous_variant	36/40
POLE	XM_011534802.4	c.3123C>T	p.Pro1041=	splice_region_variant, synonymous_variant	20/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.6135C>T	p.Pro2045=	splice_region_variant, synonymous_variant	44/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000838 AC: 21 AN: 250618 Hom.: 0 AF XY: 0.0000811 AC XY: 11 AN XY: 135648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.0000536 AC XY: 39 AN XY: 727134

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74334

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

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: 0.00

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.0000869

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 18, 2016	Variant classified as Uncertain Significance - Favor Benign. The p.Pro2045Pro va riant in POLE has not been previously reported in individuals with colorectal ca ncer but has been identified in 5/8596 of East Asian chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368662693). This variant is located in the last three bases of the exon, which is part of th e 5? splice region. Computational tools do not suggest an impact to splicing. Ho wever, this information is not predictive enough to rule out pathogenicity. In s ummary, the clinical significance of the p.Pro2045Pro variant is uncertain altho ugh it is suspected to be more likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 09, 2016	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. -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 29, 2017	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	0.14
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs368662693; hg19: chr12-133209251; COSMIC: COSV57691561; COSMIC: COSV57691561;