rs1555225201

Variant names:

• chr12-132657388-GGCGCT-CA
• rs1555225201
• NM_006231.4:c.3415_3420delAGCGCCinsTG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006231.4(POLE):​c.3415_3420delAGCGCCinsTG​(p.Ser1139fs) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: POLE NM_006231.4 frameshift, missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 9.84

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-132657388-GGCGCT-CA is Pathogenic according to our data. Variant chr12-132657388-GGCGCT-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 484563.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLE	NM_006231.4	c.3415_3420delAGCGCCinsTG	p.Ser1139fs	frameshift_variant, missense_variant	Exon 28 of 49	ENST00000320574.10	NP_006222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLE	ENST00000320574.10	c.3415_3420delAGCGCCinsTG	p.Ser1139fs	frameshift_variant, missense_variant	Exon 28 of 49	1	NM_006231.4	ENSP00000322570.5

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

May 05, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23230001, 30503519, 25948378) -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser1139*) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with POLE-related conditions. For these reasons, this variant has been classified as Pathogenic. -

POLE-related disorder Pathogenic:1

May 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLE c.3415_3420delinsTG variant is predicted to result in premature protein termination (p.Ser1139*). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Frameshift variants in POLE are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3415_3420delAGCGCCinsTG variant, located in coding exon 28 of the POLE gene, results from the deletion of 6 nucleotides and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon (p.S1139*). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although biallelic loss of function of POLE has been associated with autosomal recessive POLE deficiency, haploinsufficiency of POLE has not been established as a mechanism of disease for POLE-related polymerase proofreading-associated polyposis (PPAP) and POLE-related CMMRD-like syndrome. Based on the supporting evidence, this variant is expected to be causative of POLE deficiency when present along with a second pathogenic variant on the other allele; however, its clinical significance for PPAP and POLE-related CMMRD-like syndrome is unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555225201; hg19: chr12-133233974;