NM_006231.4(POLE):c.5636G>A (p.Arg1879His) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 13, 2016
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:: RCV000455415.4

Allele description [Variation Report for NM_006231.4(POLE):c.5636G>A (p.Arg1879His)]

NM_006231.4(POLE):c.5636G>A (p.Arg1879His)

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.5636G>A (p.Arg1879His)

HGVS:

NC_000012.12:g.132638056C>T
NG_033840.1:g.54469G>A
NM_006231.4:c.5636G>AMANE SELECT
NP_006222.2:p.Arg1879His
NP_006222.2:p.Arg1879His
LRG_789t1:c.5636G>A
LRG_789:g.54469G>A
LRG_789p1:p.Arg1879His
NC_000012.11:g.133214642C>T
NM_006231.2:c.5636G>A
NM_006231.3:c.5636G>A

Protein change:

R1879H

Links:

dbSNP: rs145621558

NCBI 1000 Genomes Browser:

rs145621558

Molecular consequence:

NM_006231.4:c.5636G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000540089	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Oct 13, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000569856	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Apr 4, 2016)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000540089

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Oct 13, 2016)

germline

clinical testing

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

SCV000569856

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Apr 4, 2016)

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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000540089.1

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

Description

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: Variant not in HGMD or ClinVar. MaxMAF is 0.11% AA not conserved in mammals - His seen in 6 non-mammals.

#	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, SCV000569856.3

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

Description

This variant is denoted POLE c.5636G>A at the cDNA level, p.Arg1879His (R1879H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Arg1879His was observed with an allele frequency of 0.4% (5/1322) in the African populations in 1000 Genomes. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. POLE Arg1879His occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is not located in a known functional domain (Preston 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLE Arg1879His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#	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: Oct 8, 2024

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