NM_006231.4(POLE):c.1370C>T (p.Thr457Met) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 8, 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:: RCV001550596.5

Allele description [Variation Report for NM_006231.4(POLE):c.1370C>T (p.Thr457Met)]

NM_006231.4(POLE):c.1370C>T (p.Thr457Met)

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.1370C>T (p.Thr457Met)

HGVS:

NC_000012.12:g.132673267G>A
NG_033840.1:g.19258C>T
NM_006231.4:c.1370C>TMANE SELECT
NP_006222.2:p.Thr457Met
NP_006222.2:p.Thr457Met
LRG_789t1:c.1370C>T
LRG_789:g.19258C>T
LRG_789p1:p.Thr457Met
NC_000012.11:g.133249853G>A
NM_006231.2:c.1370C>T
NM_006231.3:c.1370C>T

Protein change:

T457M

Links:

dbSNP: rs878854842

NCBI 1000 Genomes Browser:

rs878854842

Molecular consequence:

NM_006231.4:c.1370C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000289253	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 8, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32567205, 32992294, 28492532
SCV001770945	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jan 20, 2020)	germline	clinical testing	Citation Link,
SCV004219078	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Feb 8, 2023)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25124163, 25860647, 30917185, 32567205, 32992294, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000289253

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 8, 2024)

germline

clinical testing

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

SCV001770945

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jan 20, 2020)

germline

clinical testing

Citation Link,

SCV004219078

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Feb 8, 2023)

unknown

clinical testing

PubMed (6)
[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	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
not provided	unknown	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

Mutations in POLE and survival of colorectal cancer patients--link to disease stage and treatment.

Stenzinger A, Pfarr N, Endris V, Penzel R, Jansen L, Wolf T, Herpel E, Warth A, Klauschen F, Kloor M, Roth W, Bläker H, Chang-Claude J, Brenner H, Hoffmeister M, Weichert W.

Cancer Med. 2014 Dec;3(6):1527-38. doi: 10.1002/cam4.305. Epub 2014 Aug 1.

PubMed [citation]

PMID:: 25124163
PMCID:: PMC4298379

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000289253.7

#	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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 457 of the POLE protein (p.Thr457Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer and/or thyroid cancer (PMID: 32567205, 32992294). ClinVar contains an entry for this variant (Variation ID: 240390). 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 not expected to disrupt POLE protein function with a negative predictive value of 80%. 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

From GeneDx, SCV001770945.1

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

Description

Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32567205, 32992294, 25124163, 25860647, 30917185)

#	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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219078.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This variant has not been described in online databases. The frequency of this variant in the general population, 0.000013 (2/152254 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with thyroid cancer (PMID: 32992294 (2020)) and colorectal cancer (PMID: 32567205 (2020)). The variant has also been reported as a somatic variant in endometrial (PMID: 30917185 (2019)) and colorectal cancer tumors (PMID: 25124163 (2014)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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

Last Updated: Sep 29, 2024

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