rs869312803

chr12-132676173-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_006231.4(POLE):c.941C>G(p.Ser314Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S314S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: POLE NM_006231.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5 B:1
• Conservation: PhyloP100: 9.95

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLE	NM_006231.4	c.941C>G	p.Ser314Ter	stop_gained	10/49	ENST00000320574.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLE	ENST00000320574.10	c.941C>G	p.Ser314Ter	stop_gained	10/49	1	NM_006231.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460984 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 27, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with breast cancer (Shirts et al., 2016); This variant is associated with the following publications: (PMID: 27244218, 29056344, 26845104) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 19, 2023	This sequence change creates a premature translational stop signal (p.Ser314*) in the POLE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224590). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Colorectal cancer, susceptibility to, 12 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Oct 30, 2017	A large study of hypermutated tumors describes specific missense driver mutations in POLE (Campbell 2017). Variants in POLE that increase cancer risk cause increased mutations in replicating DNA by specifically altering the exonuclease, or proofreading, activity while maintaining the polymerase, or DNA synthesis, activity of this enzyme Truncating variants that eliminate all polymerase activity are not predicted to produce a similar hypermutation phenotype. Consistently, there are no reported observations of truncating variants in the POLE gene, such as p.S314*, causing hypermutation in tumors with increased cancer risk. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 21, 2017

The p.Ser314X variant in POLE has been reported in 1 individual with breast canc er (Shirts 2015), has also been reported in ClinVar (Variation ID 224590) and wa s absent from large population studies. This nonsense variant leads to a prematu re termination codon at position 314, which is predicted to lead to a truncated or absent protein. Although this variant is expected to severely impact the prot ein, the POLE gene has not yet been widely studied in patients (to date, virtual ly all variants reported in patients with colorectal cancer represent missense c hanges). In summary, the clinical significance of the p.Ser314X variant is uncer tain. -

POLE-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2022

The POLE c.941C>G variant is predicted to result in premature protein termination (p.Ser314*). This variant has been reported as a variant of uncertain significance in an individual with breast cancer (Table S1 - Shirts et al. 2016. PubMed ID: 26845104). This variant is not present in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Missense variants that disrupt the proofreading, but not the polymerase, activity of the POLE protein have been predominantly implicated in colorectal adenomas and carcinomas (Palles et al. 2013, PubMed ID: 23263490; Briggs & Tomlinson 2013. PubMed ID: 23447401). The effect of truncating variants that would significantly disrupt or abolish POLE protein function is unclear (Lorca et al. 2019. PubMed ID: 31285513; ClinVar). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2019

The p.S314* variant (also known as c.941C>G), located in coding exon 10 of the POLE gene, results from a C to G substitution at nucleotide position 941. This changes the amino acid from a serine to a stop codon within coding exon 10. This alteration has been reported as a variant of uncertain significance in a patient with breast cancer from a cohort of 1,462 sequential patients referred for testing by multi-gene panels (Shirts BH et al. Genet. Med. 2016 10;18:974-81). This region is highly conserved in available vertebrate species. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay; however, loss of function of POLE has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	40
Dann	Uncertain	0.99
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.88
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs869312803; hg19: chr12-133252759;