NM_006231.4(POLE):c.6445C>T (p.Arg2149Cys) AND Colorectal cancer, susceptibility to, 12

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 7, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000476996.18

Allele description [Variation Report for NM_006231.4(POLE):c.6445C>T (p.Arg2149Cys)]

NM_006231.4(POLE):c.6445C>T (p.Arg2149Cys)

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.6445C>T (p.Arg2149Cys)

Other names:

p.Arg2149Cys

HGVS:

NC_000012.12:g.132626203G>A
NG_033840.1:g.66322C>T
NM_006231.4:c.6445C>TMANE SELECT
NP_006222.2:p.Arg2149Cys
NP_006222.2:p.Arg2149Cys
LRG_789t1:c.6445C>T
LRG_789:g.66322C>T
LRG_789p1:p.Arg2149Cys
NC_000012.11:g.133202789G>A
NM_006231.2:c.6445C>T
NM_006231.3:c.6445C>T

Protein change:

R2149C

Links:

dbSNP: rs771490182

NCBI 1000 Genomes Browser:

rs771490182

Molecular consequence:

NM_006231.4:c.6445C>T - 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
SCV002584930	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Oct 3, 2022)	germline	clinical testing	Citation Link,
SCV004015274	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 7, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002584930

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Uncertain significance
(Oct 3, 2022)

germline

clinical testing

Citation Link,

SCV004015274

KCCC/NGS Laboratory, Kuwait Cancer Control Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 7, 2023)

unknown

clinical testing

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

Help

Summary from all submissions

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV002584930.1

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

Description

The POLE c.6445C>T (p.Arg2149Cys) missense change has a maximum subpopulation frequency of 0.059% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as 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 KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004015274.1

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

Description

A variant of uncertain significance was detected at POLE gene (c.6445C>T). This sequence change replaces arginine with cysteine at codon 2149 of the POLE protein (p.Arg2149Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs771490182, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains an entry for this variant (Variation ID: 405704). In-silico predictions show benign computational verdict based on 8 benign predictions from BayesDel_addAF, DEOGEN2, EIGEN, M-CAP, MVP, MutationAssessor, PrimateAI and SIFT vs 4 pathogenic predictions from DANN, FATHMM-MKL, LIST-S2 and MutationTaster but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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