VCV000380209.37 - ClinVar

NM_006231.4(POLE):c.910-6G>C

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.

(14)

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.

Benign

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.910-6G>C

Variation ID: 380209 Accession: VCV000380209.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.33 12: 132676210 (GRCh38) [ NCBI UCSC ] 12: 133252796 (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	Mar 8, 2017	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006231.4:c.910-6G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NC_000012.12:g.132676210C>G
NC_000012.11:g.133252796C>G
NG_033840.1:g.16315G>C
LRG_789:g.16315G>C
LRG_789t1:c.910-6G>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000012.12:132676209:C:G

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.

0.42832 (C)

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

1000 Genomes Project 30x 0.56761

1000 Genomes Project 0.57169

The Genome Aggregation Database (gnomAD) 0.64353

Trans-Omics for Precision Medicine (TOPMed) 0.64580

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.68215

Links

ClinGen: CA6894139 dbSNP: rs4077170 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	9159	9372

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 specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Oct 3, 2016	RCV000440217.20
not provided	Benign (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000586907.24
Colorectal cancer, susceptibility to, 12	Benign (1)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV001080794.15
Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency	Benign (1)	criteria provided, single submitter	Oct 25, 2021	RCV001789327.10
Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	Benign (1)	criteria provided, single submitter	Oct 25, 2021	RCV001789326.10
Hereditary cancer-predisposing syndrome	Benign (1)	criteria provided, single submitter	May 19, 2015	RCV002374643.9

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.
Benign (Mar 29, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000540085.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency (less) Method: Genome/Exome Filtration
Benign (May 25, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698689.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Comment: Variant summary: The POLE c.910-6G>C intronic variant involves the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant … (more) Variant summary: The POLE c.910-6G>C intronic variant involves the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant along with 5/5 splice site tools predicting the variant to to have an impact on normal splicing. This variant was found in 76218/120852 control chromosomes (24815 homozygotes) at a frequency of 0.6306722 suggesting the variant to be the ancestral allele and a benign polymorphism. Taken together, this variant is classified as Benign. (less)
Benign (Oct 29, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000517991.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: 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 … (more) 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. (less)
Benign (Oct 03, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000806860.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Benign (Feb 01, 2024)	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: SCV001000912.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024
Benign (Oct 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002031659.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021
Benign (Oct 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002031660.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, susceptibility to, 12 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016681.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (Nov 30, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001470788.7 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Benign (May 19, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002684747.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: 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 … (more) 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. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005237704.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001923297.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954375.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002074728.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022	Comment: Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. (less) Clinical Features: Phenotypic abnormality (present) Indication for testing: Diagnostic Age: 40-49 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-04-27 Testing laboratory interpretation: Benign
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Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Comment:

Variant summary: The POLE c.910-6G>C intronic variant involves the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant along with 5/5 splice site tools predicting the variant to to have an impact on normal splicing. This variant was found in 76218/120852 control chromosomes (24815 homozygotes) at a frequency of 0.6306722 suggesting the variant to be the ancestral allele and a benign polymorphism. Taken together, this variant is classified as Benign.

Comment:

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.

Comment:

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.

Comment:

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs4077170 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_006231.4(POLE):c.910-6G>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs4077170 ...