NM_006231.4(POLE):c.1270C>G (p.Leu424Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 9, 2020
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:: RCV000570294.4

Allele description [Variation Report for NM_006231.4(POLE):c.1270C>G (p.Leu424Val)]

NM_006231.4(POLE):c.1270C>G (p.Leu424Val)

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.1270C>G (p.Leu424Val)

HGVS:

NC_000012.12:g.132673664G>C
NG_033840.1:g.18861C>G
NM_006231.4:c.1270C>GMANE SELECT
NP_006222.2:p.Leu424Val
NP_006222.2:p.Leu424Val
LRG_789t1:c.1270C>G
LRG_789:g.18861C>G
LRG_789p1:p.Leu424Val
NC_000012.11:g.133250250G>C
NM_006231.2:c.1270C>G
NM_006231.3:c.1270C>G
Q07864:p.Leu424Val

Protein change:

L424V; LEU424VAL

Links:

UniProtKB: Q07864#VAR_069344; OMIM: 174762.0001; dbSNP: rs483352909

NCBI 1000 Genomes Browser:

rs483352909

Molecular consequence:

NM_006231.4:c.1270C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000671525	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Nov 9, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16699561, 23263490, 24501277, 25370038, 25529843 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000671525

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Nov 9, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

A method to select for mutator DNA polymerase deltas in Saccharomyces cerevisiae.

Murphy K, Darmawan H, Schultz A, Fidalgo da Silva E, Reha-Krantz LJ.

Genome. 2006 Apr;49(4):403-10.

PubMed [citation]

PMID:: 16699561

Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.

Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I, Sherborne A, Chubb D, Carvajal-Carmona LG, Ma Y, Kaur K, Dobbins S, Barclay E, Gorman M, Martin L, Kovac MB, Humphray S; CORGI Consortium.; et al.

Nat Genet. 2013 Feb;45(2):136-44. doi: 10.1038/ng.2503. Epub 2012 Dec 23. Erratum in: Nat Genet. 2013 Jun;45(6):713. Guarino Almeida, Estrella [corrected to Guarino, Estrella].

PubMed [citation]

PMID:: 23263490
PMCID:: PMC3785128

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000671525.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

The p.L424V pathogenic mutation (also known as c.1270C>G), located in coding exon 13 of the POLE gene, results from a C to G substitution at nucleotide position 1270. The leucine at codon 424 is replaced by valine, an amino acid with highly similar properties. This highly conserved residue is in the active site of the exonuclease domain of the POLE protein, and this alteration is predicted to affect the nuclear activity by distorting the packing of helices involved in the exonuclease active site (Palles C et al. Nat. Genet. 2013 Feb; 45(2):136-44). This mutation has been reported as one of the most commonly identified POLE mutations in familial colorectal cancer and polyposis patients. It has been shown to segregate with disease in multiple unrelated families and has not been reported in over six thousand controls or in population cohorts. In addition it has been reported as a de novo occurrence in two individuals (Spier I et al. Int. J. Cancer. 2015 Jul;137(2):320-31; Palles C et al. Nat. Genet. 2013 Feb; 45(2):136-44. Valle L et al. Hum. Mol. Genet. 2014 Jul; 23(13):3506-12. Elsayed FA et al. Eur. J. Hum. Genet. 2015 Aug; 23(8):1080-4). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Apr 15, 2024

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