Genetic Information

Gene & Transcript Details

Gene
POLD1
Transcript
NM_002691.4 MANE Select
Total Exons
—
Reference Sequence
NC_000019.9
Alternative Transcripts
IDStatusDetails
NM_002691.2 Alternative 3470 nt | 57–3380
NM_002691.4 MANE Select 3436 nt | 46–3369
NM_002691.1 Alternative 3443 nt | 54–3377
NM_002691.3 Alternative 3464 nt | 70–3393

Variant Details

HGVS Notation
NM_002691.4:c.2041del
Protein Change
L681Sfs*13
Location
Exon 17 (Exon 17 of )
17
5'Exon Structure3'
Functional Consequence
Loss of Function
Alternate Identifiers
—

Clinical & Population Data

Population Frequency

gnomAD
Global Frequency
0.0 in 100,000
Extremely Rare
ACMG Criteria Applied PM2
This variant is absent or extremely rare in population databases (PM2 criteria applies).

ClinVar

Open
Classification
Uncertain Significance (VUS)
1 publications
Publications List
PMID: 23263490

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. ClinVar contains an entry for this variant (Variation ID: 864276). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu681Serfs*13) in the POLD1 gene. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein are associated with PPAP (polymerase proofreading–associated polyposis) (PMID: 23263490, 23447401). However, loss-of-function variants that result in an absent or severely disrupted POLD1 protein, and missense variants outside the exonuclease domain, are unlikely to be associated with PPAP.

Clinical Statement

"This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories)."

COSMIC Somatic Evidence

Open
COSMIC ID
Recurrence
0 occurrences
PM1 Criteria
Not Applied
COSMIC Database Preview
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Functional Impact & Domains

Functional Domain

Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain.
Related Variants in This Domain
No evidence of other pathogenic variants at this position in gene POLD1.

Functional Studies & Therapeutic Relevance

Functional Summary

Error in OpenAI Consolidation. OncoKB: POLD1L681Sfs*13POLD1L681Sfs*13SomaticNCBI Gene:5424|Show additional gene information Variant OverviewPOLD1, a DNA polymerase, is infrequently altered by mutation in cancer.The POLD1 L681Sfs*13 mutation has not specifically been reviewed by the OncoKB team, and therefore its biological significance is unknown. JAX-CKB: No results found

Database Previews
OncoKB
OncoKB Preview
JAX-CKB
JAX-CKB Preview

Click on previews to view full database entries. External databases may require institutional access.

Computational Analysis

Pathogenicity Predictions

SpliceAI
Predictor Consensus
Unknown
PP3 Applied
No
REVEL Score
0.0
Threshold: ≥0.75 = PP3 applied

SpliceAI Scores

Window: ±500bp
Effect Type Score Position
- Acceptor Loss (AL) 0.01 -481 bp
- Donor Loss (DL) 0.01 46 bp
+ Acceptor Gain (AG) 0.03 433 bp
+ Donor Gain (DG) 0.02 85 bp
High impact (≥0.5) Medium impact (0.2-0.49) Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)

Filter Criteria:
PVS1

PVS1 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

PM2

PM2 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)