ClinVar Genomic variation as it relates to human health
NM_002691.4(POLD1):c.1816C>A (p.Leu606Met)
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.
Pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002691.4(POLD1):c.1816C>A (p.Leu606Met)
Variation ID: 568163 Accession: VCV000568163.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.33 19: 50408825 (GRCh38) [ NCBI UCSC ] 19: 50912082 (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 Oct 10, 2018 Feb 14, 2024 Oct 13, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002691.4:c.1816C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002682.2:p.Leu606Met missense NM_001256849.1:c.1816C>A NP_001243778.1:p.Leu606Met missense NM_001308632.1:c.1894C>A NP_001295561.1:p.Leu632Met missense NR_046402.2:n.1861C>A non-coding transcript variant NC_000019.10:g.50408825C>A NC_000019.9:g.50912082C>A NG_033800.1:g.29503C>A LRG_785:g.29503C>A LRG_785t1:c.1816C>A LRG_785p1:p.Leu606Met LRG_785t2:c.1894C>A LRG_785p2:p.Leu632Met - Protein change
- L606M, L632M
- Other names
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- Canonical SPDI
- NC_000019.10:50408824:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on protein activity Variation Ontology [VariO:0053]
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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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- Links
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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POLD1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4875 | 4924 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 13, 2022 | RCV000688430.9 |
Submissions - Germline
Classification
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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
(Jan 25, 2022)
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criteria provided, single submitter
Method: clinical testing, in vitro
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Colorectal cancer, susceptibility to, 10
(Autosomal dominant inheritance)
Affected status: yes, not applicable
Allele origin:
germline,
not applicable
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Hereditary Cancer Clinic, Medical College of Georgia
Accession: SCV002064260.1
First in ClinVar: Jun 16, 2022 Last updated: Jun 16, 2022 |
Comment:
PS2 De novo. (Proband VAF 14%, unaffected mother tested negative.) PS3 Well-established in vitro or in vivo functional studies. (Yeast cell lines with same amino … (more)
PS2 De novo. (Proband VAF 14%, unaffected mother tested negative.) PS3 Well-established in vitro or in vivo functional studies. (Yeast cell lines with same amino acid change show deleterious effect in base incorporation and polymerase-exonuclease switching rate.) PM1. Located in a mutational hot spot and/or critical and well-established. (Located in polymerase domain.) PM2. Variant not found in gnomAD exomes. PP1. Co-segregation with disease. PP3. Multiple lines of computational evidence support a deleterious effect. PP4. Patient’s phenotype or family history is highly specific. (Polyposis phenotype.) (less)
Observation 1:
Number of individuals with the variant: 3
Age: 16-39 years
Sex: female
Ethnicity/Population group: Black
Comment on evidence:
Polyposis (distribution gastric to rectum, endometrium) Mother (PROBAND, affected, likely mosaic) also with multiple gastrointestinal adenocarcinomas Two daughters (heterozygous) with gastrointestinal polyps Proband's mother unaffected … (more)
Polyposis (distribution gastric to rectum, endometrium) Mother (PROBAND, affected, likely mosaic) also with multiple gastrointestinal adenocarcinomas Two daughters (heterozygous) with gastrointestinal polyps Proband's mother unaffected and tested negative Adenomas show elevated tumor mutation burden (less)
Testing laboratory: Invitae (6/12/19), Caris
Testing laboratory interpretation: Uncertain significance
Observation 2:
Comment on evidence:
PMID: 17121822 See also adjacent-residue study in HCT-116 human cells PMID: 28368425
Result:
Conserved amino acid. Same alteration (L612M) shows elevated base mis-incorporation and polymerase-exonuclease switching leading to elevated spontaneous mutation rate.
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Uncertain significance
(Oct 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, susceptibility to, 10
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000816040.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POLD1 function (PMID: 23245697, 25217194). In summary, the available … (more)
Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POLD1 function (PMID: 23245697, 25217194). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 POLD1 protein function. ClinVar contains an entry for this variant (Variation ID: 568163). This missense change has been observed in individual(s) with colorectal polyps and colorectal cancer (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 606 of the POLD1 protein (p.Leu606Met). (less)
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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effect on protein activity
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Hereditary Cancer Clinic, Medical College of Georgia
Accession: SCV002064260.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Nucleotide selectivity defect and mutator phenotype conferred by a colon cancer-associated DNA polymerase δ mutation in human cells. | Mertz TM | Oncogene | 2017 | PMID: 28368425 |
Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. | Shlien A | Nature genetics | 2015 | PMID: 25642631 |
Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition. | Lujan SA | Genome research | 2014 | PMID: 25217194 |
Ribonucleotide incorporation, proofreading and bypass by human DNA polymerase δ. | Clausen AR | DNA repair | 2013 | PMID: 23245697 |
Inefficient proofreading and biased error rates during inaccurate DNA synthesis by a mutant derivative of Saccharomyces cerevisiae DNA polymerase delta. | Nick McElhinny SA | The Journal of biological chemistry | 2007 | PMID: 17121822 |
Text-mined citations for rs1568630225 ...
HelpRecord last updated Feb 14, 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.