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POLD1c.2041delLikely pathogenic
Print report
Variant interpretation report

POLD1 c.2041del, p.(Leu681SerfsTer13)

NM_002691.4:c.2041del NP_002682.2:p.(Leu681SerfsTer13) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About POLD1

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

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.

PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,613,242 alleles

gnomAD v4.1: 1 / 1,613,242 alleles. Recorded AF 6.1987e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 4 not met · 10 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

No reviewed variant-specific functional studies were identified for this frameshift variant in the retrieved functional evidence sources.

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.

Met · 2

PVS1 Very strongThis 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. Details ▾Hide ▴
Evidence considered
  • Frameshift predicted as NP_002682.2:p.(Leu681SerfsTer13)
  • Generic PVS1 scaffold recommends default PVS1 for frameshift variants
  • Gene-level PVS1 gate marked eligible with loss-of-function mechanism supported
Still missing
  • No gene-specific POLD1 VCEP or local PVS1 specification was available.
  • Transcript relevance and any exon-specific caveats should still be confirmed by human review.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • gnomAD v4.1 AF 6.198698025466731e-07 overall
  • best subpopulation AF 8.474533180339761e-07
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

PM1 Cancer Hotspots did not identify this variant or residue as a statistically significant hotspot, so PM1 is not met. Details ▾Hide ▴
Evidence considered
  • No hotspot row found for POLD1 L681
Sources
hotspots ↗
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. Details ▾Hide ▴
Evidence considered
  • Best subpopulation AF 8.474533180339761e-07
Sources
gnomad_v4 ↗
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. Details ▾Hide ▴
Evidence considered
  • Best subpopulation AF 8.474533180339761e-07
Sources
gnomad_v4 ↗
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. Details ▾Hide ▴
Evidence considered
  • 1/1613242 alleles in gnomAD v4.1
  • homozygotes 0
Still missing
  • No phenotype-confirmed unaffected carrier data were identified.
Sources
gnomad_v4 ↗

Not assessed · 10 · no assessment recorded

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Evidence considered
  • ClinVar exact variant record reviewed
Still missing
  • No de novo case report was identified.
Sources
clinvar ↗
PS3 No well-established variant-specific functional studies demonstrating a damaging effect were identified for this frameshift variant, so PS3 was not assessed. Details ▾Hide ▴
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence
Still missing
  • No reviewed variant-specific functional assay evidence was identified.
Sources
oncokb ↗
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. Details ▾Hide ▴
Evidence considered
  • ClinVar lists uncertain significance submissions only
Still missing
  • No affected-case enrichment data were identified.
Sources
clinvar ↗
PM6 No presumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Evidence considered
  • ClinVar exact variant record reviewed
Still missing
  • No presumed de novo report was identified.
Sources
clinvar ↗
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Evidence considered
  • No segregation details in reviewed ClinVar summary
Still missing
  • No informative meioses or pedigree data were identified.
Sources
clinvar ↗
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. Details ▾Hide ▴
Still missing
  • No case-level phenotype data were available.
BS3 No well-established variant-specific functional studies showing a normal or benign effect were identified, so BS3 was not assessed. Details ▾Hide ▴
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence
Still missing
  • No benign functional assay evidence was identified.
Sources
oncokb ↗
BS4 No nonsegregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Evidence considered
  • No family nonsegregation details in reviewed ClinVar summary
Still missing
  • No unaffected-carrier or nonsegregation family report was identified.
Sources
clinvar ↗
BP2 No phase data with another variant were identified, so BP2 was not assessed. Details ▾Hide ▴
Still missing
  • No cis/trans observations with another variant were identified.
BP5 No alternate molecular diagnosis explaining the phenotype was identified, so BP5 was not assessed. Details ▾Hide ▴
Still missing
  • No comprehensive alternate-diagnosis data were available.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to a different nucleotide change causing the same amino acid substitution. This variant is a frameshift, so PS1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
PM3 N/APM3 is used for recessive disorders with pathogenic variants observed in trans. That evidence was not relevant for this POLD1 evaluation, so PM3 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 is intended for protein length changes caused by in-frame deletions/insertions or stop-loss variants. This variant is a frameshift and is captured by PVS1 instead, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant bucket is frameshift
Sources
pvs1_variant_assessment
PM5 N/APM5 applies to a novel missense change at a residue where a different pathogenic missense change is established. This variant is a frameshift, so PM5 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
PP2 N/APP2 is a missense-specific criterion and does not apply to this frameshift variant. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
PP3 N/AREVEL and BayesDel were not applicable because this is not a single-nucleotide missense variant, and HCI prior is not available for POLD1. SpliceAI showed a low maximum delta score of 0.03, below commonly used splicing concern thresholds, but this frameshift is already addressed through PVS1 rather than a separate PP3 call. Details ▾Hide ▴
Evidence considered
  • REVEL skipped: not SNV
  • BayesDel skipped: not SNV
  • HCI prior not available for POLD1
  • SpliceAI max delta score 0.03
Sources
spliceai ↗pvs1_variant_assessment
PP5 N/APP5 was not used because external assertions without independently reviewable evidence are not applied in this evaluation. Details ▾Hide ▴
Evidence considered
  • ClinVar classification reviewed independently rather than used as PP5 evidence
Sources
clinvar ↗
BP1 N/ABP1 is a missense-specific criterion and does not apply to this frameshift variant. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
BP3 N/ABP3 applies to in-frame variants in repetitive regions without known function. This variant is a frameshift, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
BP4 N/AREVEL and BayesDel were not applicable because this is not a single-nucleotide missense variant, and HCI prior is not available for POLD1. SpliceAI predicted no significant splice impact with a maximum delta score of 0.03, but BP4 was not applied because the variant is a frameshift and computational evidence is not being used as a separate benign criterion here. Details ▾Hide ▴
Evidence considered
  • REVEL skipped: not SNV
  • BayesDel skipped: not SNV
  • HCI prior not available for POLD1
  • SpliceAI max delta score 0.03
Sources
spliceai ↗
BP6 N/ABP6 was not used because external benign assertions without independently reviewable evidence are not applied in this evaluation. Details ▾Hide ▴
Evidence considered
  • ClinVar reviewed independently rather than used as BP6 evidence
Sources
clinvar ↗
BP7 N/ABP7 applies to synonymous or certain noncoding variants with no predicted splice impact. This variant is a coding frameshift, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
  • SpliceAI reviewed but criterion is not applicable to this variant class
Sources
spliceai ↗

Identifiers

Gene
POLD1
Transcript
NM_002691.4
Coding (HGVS c.)
NM_002691.4:c.2041del
Protein (HGVS p.)
NP_002682.2:p.(Leu681SerfsTer13)
GRCh38
chr19:50409548 AC>A
GRCh37
chr19:50912805 AC>A

Gene diagram

Every interpreted variant in POLD1, mapped onto the exon structure of NM_002691.4. Select a row to find it on the plot.

POLD1NM_002691.4
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,613,242 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,613,242 alleles · 0 hom
European (non-Finnish)1 / 1,180,006 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/AREVEL and BayesDel were not applicable because this is not a single-nucleotide missense variant, and HCI prior is not available for POLD1. SpliceAI showed a low maximum delta score of 0.03, below commonly used splicing concern thresholds, but this frameshift is already addressed through PVS1 rather than a separate PP3 call. Details ▾Hide ▴
Evidence considered
  • REVEL skipped: not SNV
  • BayesDel skipped: not SNV
  • HCI prior not available for POLD1
  • SpliceAI max delta score 0.03
Sources
spliceai ↗pvs1_variant_assessment
BP4 N/AREVEL and BayesDel were not applicable because this is not a single-nucleotide missense variant, and HCI prior is not available for POLD1. SpliceAI predicted no significant splice impact with a maximum delta score of 0.03, but BP4 was not applied because the variant is a frameshift and computational evidence is not being used as a separate benign criterion here. Details ▾Hide ▴
Evidence considered
  • REVEL skipped: not SNV
  • BayesDel skipped: not SNV
  • HCI prior not available for POLD1
  • SpliceAI max delta score 0.03
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous or certain noncoding variants with no predicted splice impact. This variant is a coding frameshift, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • Variant type is frameshift
  • SpliceAI reviewed but criterion is not applicable to this variant class
Sources
spliceai ↗

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,613,242 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

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

In silico

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

Functional

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.

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.