VCV002752061.2 - ClinVar

NM_006231.4(POLE):c.62+1G>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006231.4(POLE):c.62+1G>A

Variation ID: 2752061 Accession: VCV002752061.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.33 12: 132687253 (GRCh38) [ NCBI UCSC ] 12: 133263839 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 14, 2024	Apr 20, 2024	Jan 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006231.4:c.62+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000012.12:g.132687253C>T
NC_000012.11:g.133263839C>T
NG_033840.1:g.5272G>A
NG_187616.1:g.561C>T
LRG_789:g.5272G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000012.12:132687252:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
POLE		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	9156	9369
LOC130009266	-	-	-	GRCh38	-	187

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (1)	criteria provided, single submitter	Jan 26, 2023	RCV003571174.2
Polymerase proofreading-related adenomatous polyposis	Likely pathogenic (1)	criteria provided, single submitter	Nov 3, 2022	RCV004017995.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004316554.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 29754823‚ 30503519 Comment: This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the POLE … (more) This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the POLE gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Disruption of this splice site has been observed in individual(s) with autosomal recessive POLE-related conditions (PMID: 29754823, 30503519). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Likely Pathogenic (Nov 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Polymerase proofreading-related adenomatous polyposis Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848857.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The c.62+1G>A variant in POLE has not been reported in individuals with disease and was absent from large population studies. This variant occurs within the … (more) The c.62+1G>A variant in POLE has not been reported in individuals with disease and was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the POLE gene is an established disease mechanism in autosomal dominant polymerase proofreading-related adenomatous polyposis. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant polymerase proofreading-related adenomatous polyposis. ACMG/AMP Criteria applied: PVS1, PM2_Supporting. (less)

Comment:

This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the POLE gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Disruption of this splice site has been observed in individual(s) with autosomal recessive POLE-related conditions (PMID: 29754823, 30503519). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.62+1G>A variant in POLE has not been reported in individuals with disease and was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the POLE gene is an established disease mechanism in autosomal dominant polymerase proofreading-related adenomatous polyposis. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant polymerase proofreading-related adenomatous polyposis. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.	Logan CV	American journal of human genetics	2018	PMID: 30503519
Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis.	Bellelli R	Molecular cell	2018	PMID: 29754823

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_006231.4(POLE):c.62+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...