NM_006231.4(POLE):c.857C>G (p.Pro286Arg) AND Colorectal cancer, susceptibility to, 12

Clinical significance:Uncertain significance (Last evaluated: Feb 1, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000532834.1

Allele description [Variation Report for NM_006231.4(POLE):c.857C>G (p.Pro286Arg)]

NM_006231.4(POLE):c.857C>G (p.Pro286Arg)

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.857C>G (p.Pro286Arg)
HGVS:
  • NC_000012.12:g.132676598G>C
  • NG_033840.1:g.15927C>G
  • NM_006231.3:c.857C>G
  • NM_006231.4:c.857C>GMANE SELECT
  • NP_006222.2:p.Pro286Arg
  • NP_006222.2:p.Pro286Arg
  • LRG_789t1:c.857C>G
  • LRG_789:g.15927C>G
  • LRG_789p1:p.Pro286Arg
  • NC_000012.11:g.133253184G>C
  • NM_006231.2:c.857C>G
Protein change:
P286R
Links:
dbSNP: rs1057519943
NCBI 1000 Genomes Browser:
rs1057519943
Molecular consequence:
  • NM_006231.3:c.857C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006231.4:c.857C>G - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000653485Invitaecriteria provided, single submitter
Uncertain significance
(Feb 1, 2017)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000653485.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces proline with arginine at codon 286 of the POLE protein (p.Pro286Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in the germline of individuals with a POLE-related disease, however, it has been reported as a frequent somatic change in endometrial and colorectal cancers (PMID: 23263490, 23447401, 25224212, 24525744). This variant is located within the evolutionarily conserved exonuclease domain of the POLE protein (PMID: 23447401, 24525744). Experimental studies have shown that the P301R yeast mutant, corresponding to the p.Pro286Arg change, severely affects the fidelity rather than the proofreading function of the POLE protein, causing a strong mutator phenotype in a yeast model system (PMID: 24525744). In addition, this variant showed a reduced 3'-5' exonuclease activity compared to the wild-type protein (PMID: 25228659). In summary, this variant is a rare missense change that is not present in the population and has been shown to affect protein function. Although this variant has been found as a frequent somatic event in tumors, it has not been observed in the germline of affected individuals. In the absence of genetic and/or additional evidence, this variant has been classified as Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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