NM_006231.4(POLE):c.6136G>A (p.Gly2046Arg) AND Colorectal cancer, susceptibility to, 12

delete

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 13, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000650796.7

Allele description

NM_006231.4(POLE):c.6136G>A (p.Gly2046Arg)

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.6136G>A (p.Gly2046Arg)

HGVS:

NC_000012.12:g.132632664C>T
NG_033840.1:g.59861G>A
NM_006231.4:c.6136G>AMANE SELECT
NP_006222.2:p.Gly2046Arg
NP_006222.2:p.Gly2046Arg
LRG_789t1:c.6136G>A
LRG_789:g.59861G>A
LRG_789p1:p.Gly2046Arg
NC_000012.11:g.133209250C>T
NM_006231.2:c.6136G>A
NM_006231.3:c.6136G>A

Protein change:

G2046R

Links:

dbSNP: rs1462887616

NCBI 1000 Genomes Browser:

rs1462887616

Molecular consequence:

NM_006231.4:c.6136G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Colorectal cancer, susceptibility to, 12 (CRCS12)
Synonyms:: COLORECTAL CANCER, SUSCEPTIBILITY TO, ON CHROMOSOME 12q24
Identifiers:: MONDO: MONDO:0014038; MedGen: C3554460; Orphanet: 220460; OMIM: 615083

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000772645	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17576681, 9536098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000772645

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 13, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000772645.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2046 of the POLE protein (p.Gly2046Arg). This variant also falls at the last nucleotide of exon 44, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 540694). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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

Last Updated: Feb 4, 2024

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