NM_006231.4(POLE):c.1940A>T (p.Asp647Val) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 7, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003105910.4

Allele description [Variation Report for NM_006231.4(POLE):c.1940A>T (p.Asp647Val)]

NM_006231.4(POLE):c.1940A>T (p.Asp647Val)

Gene:

POLE:DNA polymerase epsilon, catalytic subunit [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.33

Genomic location:

Preferred name:

NM_006231.4(POLE):c.1940A>T (p.Asp647Val)

HGVS:

NC_000012.12:g.132668721T>A
NG_033840.1:g.23804A>T
NM_006231.4:c.1940A>TMANE SELECT
NP_006222.2:p.Asp647Val
NP_006222.2:p.Asp647Val
LRG_789t1:c.1940A>T
LRG_789:g.23804A>T
LRG_789p1:p.Asp647Val
NC_000012.11:g.133245307T>A
NM_006231.2:c.1940A>T
NM_006231.3:c.1940A>T

Protein change:

D647V

Links:

dbSNP: rs1060500884

NCBI 1000 Genomes Browser:

rs1060500884

Molecular consequence:

NM_006231.4:c.1940A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: Homo sapiens janus kinase and microtubule interacting protein 2 (JAKM...
PREDICTED: Homo sapiens janus kinase and microtubule interacting protein 2 (JAKMIP2), transcript variant X3, mRNA
gi|2217358048|ref|XM_047417951.1|

Nucleotide
PREDICTED: Homo sapiens rhomboid 5 homolog 1 (RHBDF1), transcript variant X5, mR...
PREDICTED: Homo sapiens rhomboid 5 homolog 1 (RHBDF1), transcript variant X5, mRNA
gi|2462550242|ref|XM_054313668.1|

Nucleotide
inactive rhomboid protein 1 isoform X2 [Homo sapiens]
inactive rhomboid protein 1 isoform X2 [Homo sapiens]
gi|2462550237|ref|XP_054169640.1|

Protein
PREDICTED: Homo sapiens rhomboid 5 homolog 1 (RHBDF1), transcript variant X4, mR...
PREDICTED: Homo sapiens rhomboid 5 homolog 1 (RHBDF1), transcript variant X4, mRNA
gi|2217307036|ref|XM_017023556.2|

Nucleotide
Helicobacter pylori strain HP98285, whole genome shotgun sequencing project
Helicobacter pylori strain HP98285, whole genome shotgun sequencing project
gi|1735182113|gb|MVTJ00000000.1|MVT 0000

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544214	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 7, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003762073	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 25, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544214

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 7, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003762073

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jan 25, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544214.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 647 of the POLE protein (p.Asp647Val). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 405887). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV003762073.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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