ClinVar Genomic variation as it relates to human health
NM_006231.4(POLE):c.1270C>G (p.Leu424Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006231.4(POLE):c.1270C>G (p.Leu424Val)
Variation ID: 40046 Accession: VCV000040046.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.33 12: 132673664 (GRCh38) [ NCBI UCSC ] 12: 133250250 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 14, 2015 Apr 15, 2024 Nov 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006231.4:c.1270C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006222.2:p.Leu424Val missense NC_000012.12:g.132673664G>C NC_000012.11:g.133250250G>C NG_033840.1:g.18861C>G LRG_789:g.18861C>G LRG_789t1:c.1270C>G LRG_789p1:p.Leu424Val Q07864:p.Leu424Val - Protein change
- L424V
- Other names
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- Canonical SPDI
- NC_000012.12:132673663:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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POLE | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
8874 | 9083 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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risk factor (1) |
criteria provided, single submitter
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Aug 1, 2015 | RCV000033144.15 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 19, 2023 | RCV000484685.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 9, 2020 | RCV000570294.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000762892.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 10, 2021 | RCV001420787.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, susceptibility to, 12
Facial dysmorphism-immunodeficiency-livedo-short stature syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893282.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Nov 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000671525.4
First in ClinVar: Jan 01, 2018 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002550191.4
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
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Pathogenic
(Jun 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001748404.14
First in ClinVar: Jul 10, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568806.4
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
Comment:
This pathogenic variant is denoted POLE c.1270C>G at the cDNA level, p.Leu424Val (L424V) at the protein level, and results in the change of a Leucine … (more)
This pathogenic variant is denoted POLE c.1270C>G at the cDNA level, p.Leu424Val (L424V) at the protein level, and results in the change of a Leucine to a Valine (CTC>GTC). POLE Leu424Val has been observed in multiple individuals with either an attenuated polyposis phenotype or a history of early onset colorectal cancer, with de novo occurrence reported in two individuals (Palles 2013, Elsayed 2014, Chubb 2015). Additionally, Spier et al. (2014) found this variant to segregate with polyposis and/or colorectal cancer diagnoses in three families. While functional assays have not specifically interrogated POLE Leu424Val, the equivalent residue has been found to have an important role in exonuclease activity in both bacteriophage and yeast systems (Hogg 2004, Murphy 2006). POLE Leu424Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. POLE Leu424Val occurs at a position that is conserved across species and is located in the Exo IV motif of the Exonuclease Domain (Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic. (less)
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Pathogenic
(May 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cystic fibrosis-gastritis-megaloblastic anemia syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001623148.1
First in ClinVar: May 23, 2021 Last updated: May 23, 2021 |
Comment:
Variant summary: POLE c.1270C>G (p.Leu424Val) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the … (more)
Variant summary: POLE c.1270C>G (p.Leu424Val) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251340 control chromosomes. c.1270C>G has been reported in the literature in multiple individuals affected with Colorectal Cancer or adenomas (e.g. Palles_2013, Chubb_2015, Elsayed_2015, Hamzaoui_2020), including at least one-de novo occurrence (e.g. Valle_2014), as well a co-segregation with disease in multiple families (e.g. Palles_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence indicating that the variant results in a significantly increased mutation rate as assessed by yeast fluctuation assays (e.g. Castellsague_2018, Hamzaoui_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic or risk factor. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000543910.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 424 of the POLE protein (p.Leu424Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 424 of the POLE protein (p.Leu424Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal adenomas and carcinomas (PMID: 23263490, 24501277, 25370038, 25529843, 27683556). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40046). 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 expected to disrupt POLE protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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risk factor
(Aug 01, 2015)
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no assertion criteria provided
Method: literature only
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COLORECTAL CANCER, SUSCEPTIBILITY TO, 12
Affected status: not provided
Allele origin:
unknown
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OMIM
Accession: SCV000056926.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2015 |
Comment on evidence:
In affected members of a family with susceptibility to colorectal cancer-12 (CRCS12; 615083), Palles et al. (2013) identified a heterozygous 1270C-G transversion in the POLE … (more)
In affected members of a family with susceptibility to colorectal cancer-12 (CRCS12; 615083), Palles et al. (2013) identified a heterozygous 1270C-G transversion in the POLE gene, resulting in a leu424-to-val (L424V) substitution at a highly conserved residue in the active site of the exonuclease (proofreading) domain. The mutant mRNA was stably expressed. Molecular modeling using yeast structures indicated that the L424V mutation will distort the packing of helices involved at the exonuclease active site, likely affecting nuclear activity. The mutation was identified by linkage analysis combined with whole-genome sequencing. Direct screening for this mutation in 3,805 individuals of European ancestry with a familial colorectal cancer, multiple adenomas, and early-onset disease resulted in the identification of 12 additional unrelated probands with the mutation. The mutation was not found in 6,721 control individuals or in 10,755 control exomes. The mutation segregated with the phenotype in each of the families; there was no evidence for a common ancestor. The phenotype was compatible with autosomal dominant inheritance of a high-penetrance predisposition to the development of colorectal adenomas and carcinomas, with a variable tendency to develop multiple and large tumors. The histologic features of the tumors were unremarkable, and all were microsatellite stable. Some tumors had additional somatic mutations, for example, in the APC (611731) or KRAS (190070) genes. Valle et al. (2014) identified a de novo heterozygous L424V mutation in the POLE gene in a 28-year-old woman with polyposis and colorectal cancer. No loss of heterozygosity at the POLE chromosomal region was found in tumor DNA. This patient was ascertained from a cohort of 858 Spanish probands with familial/early-onset CRC who underwent screening of the POLE gene, thus accounting for 0.12% of the total. Elsayed et al. (2015) identified heterozygosity for the c.1270C-G transversion (c.1270C-G, NM_006231.2) in the POLE gene, resulting in a L424V mutation, in 3 (0.25%) of 1,188 Dutch index patients with polyposis or familial colorectal cancer. In 1 patient, the mutation occurred de novo. Tumor tissue samples available from 3 patients from 2 families showed microsatellite instability and were found to have somatic mutations in the MSH2 (609309) and/or MSH6 (600678) genes. The findings indicated that POLE DNA analysis is warranted in microsatellite-unstable colorectal cancer, especially in the absence of a germline variant in DNA Mismatch repair genes. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction. | Hamzaoui N | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32424176 |
Low frequency of POLD1 and POLE exonuclease domain variants in patients with multiple colorectal polyps. | Elsayed FA | Molecular genetics & genomic medicine | 2019 | PMID: 30827058 |
Novel POLE pathogenic germline variant in a family with multiple primary tumors results in distinct mutational signatures. | Castellsagué E | Human mutation | 2019 | PMID: 30362666 |
Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy. | Johanns TM | Cancer discovery | 2016 | PMID: 27683556 |
Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. | Chubb D | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25559809 |
Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. | Spier I | International journal of cancer | 2015 | PMID: 25529843 |
Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. | Elsayed FA | European journal of human genetics : EJHG | 2015 | PMID: 25370038 |
New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. | Valle L | Human molecular genetics | 2014 | PMID: 24501277 |
Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. | Palles C | Nature genetics | 2013 | PMID: 23263490 |
A method to select for mutator DNA polymerase deltas in Saccharomyces cerevisiae. | Murphy K | Genome | 2006 | PMID: 16699561 |
Text-mined citations for rs483352909 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.