Classification rationale

PVS1PM2 Likely Pathogenic

POLD1 c.2041del

The POLD1 NM_002691.4:c.2041del (p.(Leu681SerfsTer13)) variant has been reported in ClinVar, where it is classified as uncertain significance by two clinical laboratories.¹ This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1613242), which is well below the 0.1% rarity threshold used to support PM2.² No reviewed variant-specific functional studies were identified for this frameshift variant in the retrieved functional evidence sources.³ This is a truncating frameshift variant for which the generic PVS1 framework is applicable, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.⁴

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗

4 pvs1_variant_assessmentpvs1_gene_contextpvs1_generic_framework ↗spliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_002691.4 · variants mapped to exon structure

POLD1 NM_002691.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong review Pathogenic

This variant is a frameshift, NM_002691.4:c.2041del, predicted to cause p.(Leu681SerfsTer13) and truncate POLD1 well upstream of the end of the coding sequence. Available gene-level evidence supports loss of function as a disease mechanism for POLD1, and the generic ClinGen SVI PVS1 framework therefore supports applying PVS1 for this truncating variant.

Frameshift predicted as NP_002682.2:p.(Leu681SerfsTer13)Generic PVS1 scaffold recommends default PVS1 for frameshift variantsGene-level PVS1 gate marked eligible with loss-of-function mechanism supported

pvs1_generic_framework ↗

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1613242), with highest population frequency 0.00008% in European non-Finnish individuals. These values are well below the 0.1% threshold typically used for rarity, supporting PM2 at supporting strength.

Absent from gnomAD v2.1gnomAD v4.1 AF 6.198698025466731e-07 overallbest subpopulation AF 8.474533180339761e-07

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant, so PS2 was not assessed.

PS3 No well-established variant-specific functional studies demonstrating a damaging effect were identified for this frameshift variant, so PS3 was not assessed.

PS4 This variant has been reported in ClinVar, but no case-control data or multiple independent affected observations sufficient to demonstrate enrichment in affected individuals were identified, so PS4 was not assessed.

PM1 Cancer Hotspots did not identify this variant or residue as a statistically significant hotspot, so PM1 is not met.

PM6 No presumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

PP4 No detailed phenotype information specific enough to determine whether the clinical presentation is highly specific for a POLD1-related disorder was identified, so PP4 was not assessed.

Benign

BA1 The highest observed population frequency for this variant is 0.00008% in gnomAD v4.1, which is far below the 1% threshold for BA1, so BA1 is not met.

BS1 The highest observed population frequency for this variant is 0.00008% in gnomAD v4.1, which is well below the 0.3% threshold used for BS1, so BS1 is not met.

BS2 This variant was observed only once in gnomAD v4.1 and no homozygotes were reported, which does not provide the healthy adult observations required for BS2, so BS2 is not met.

BS3 No well-established variant-specific functional studies showing a normal or benign effect were identified, so BS3 was not assessed.

BS4 No nonsegregation data were identified for this variant, so BS4 was not assessed.

BP2 No phase data with another variant were identified, so BP2 was not assessed.

BP5 No alternate molecular diagnosis explaining the phenotype was identified, so BP5 was not assessed.

N/A · 12 PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP5 · BP1 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.1987e-07; MAF= 0.00006%, 1/1613242 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47453e-07; MAF= 0.00008%, 1/1180006 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,613,242
0 hom

European (non-Finnish)

1 / 1,180,006

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

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

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLD1, a DNA polymerase, is infrequently altered by mutation in cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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