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NM_006231.4(POLE):c.6674G>A (p.Arg2225His) AND Carcinoma of colon

Germline classification:
Uncertain significance (1 submission)
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV001357188.2

Allele description [Variation Report for NM_006231.4(POLE):c.6674G>A (p.Arg2225His)]

NM_006231.4(POLE):c.6674G>A (p.Arg2225His)

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.6674G>A (p.Arg2225His)
HGVS:
  • NC_000012.12:g.132624978C>T
  • NG_033840.1:g.67547G>A
  • NM_006231.4:c.6674G>AMANE SELECT
  • NP_006222.2:p.Arg2225His
  • NP_006222.2:p.Arg2225His
  • LRG_789t1:c.6674G>A
  • LRG_789:g.67547G>A
  • LRG_789p1:p.Arg2225His
  • NC_000012.11:g.133201564C>T
  • NM_006231.2:c.6674G>A
  • NM_006231.3:c.6674G>A
Protein change:
R2225H
Links:
dbSNP: rs538875477
NCBI 1000 Genomes Browser:
rs538875477
Molecular consequence:
  • NM_006231.4:c.6674G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Carcinoma of colon (CRC)
Synonyms:
Colonic carcinoma; Colon carcinoma
Identifiers:
MONDO: MONDO:0002032; MedGen: C0699790

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001552572Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Uncertain significanceunknownclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001552572.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The POLE p.Arg2225His variant was not identified in the literature nor was it identified in the Cosmic, or MutDB databases. The variant was identified in dbSNP (ID: rs538875477) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, GeneDx). The variant was identified in control databases in 19 of 276514 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23978 chromosomes (freq: 0.0001), Latino in 5 of 34404 chromosomes (freq: 0.0002), European in 11 of 126158 chromosomes (freq: 0.0001), and Finnish in 1 of 25742 chromosome (freq: 0.00004); it was not observed in the Other, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Arg2225 residue is conserved in in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 13, 2025