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POLD1c.2716_2717delUncertain significance
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Variant interpretation report

POLD1 c.2716_2717del, p.(Arg906AspfsTer47)

NM_002691.4:c.2716_2717del NP_002682.2:p.(Arg906AspfsTer47) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

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

NM_002691.4:c.2716_2717del is a frameshift variant in exon 21 of 27 coding exons, predicted to cause a premature termination codon (NP_002682.2:p.(Arg906AspfsTer47)) subject to nonsense-mediated decay. POLD1 loss of function is an established germline disease mechanism supported by literature evidence for polymerase proofreading-associated polyposis (PPAP) and cancer predisposition. The variant meets PVS1 at full strength under the ClinGen SVI PVS1 framework (PMC6185798).

PM2Supporting
PM2 · supporting

NM_002691.4:c.2716_2717del is completely absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0.00%), far below the generic ACMG PM2 threshold of <0.1%.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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 VUS.

02The sources

Evidence at a glance

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

SpliceAI score
0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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 · 19 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002691.4:c.2716_2717del (NP_002682.2:p.(Arg906AspfsTer47)) is a frameshift variant in exon 21 of 27 coding exons of POLD1. The deletion is predicted to cause a premature termination codon subject to nonsense-mediated decay, meeting PVS1 at very strong strength under the ClinGen SVI framework (PMC6185798). POLD1 loss of function is an established germline disease mechanism for polymerase proofreading-associated polyposis and cancer predisposition.

The variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency 0.00%), meeting PM2 at supporting strength under generic ACMG/AMP 2015 criteria (threshold <0.1%).

No additional pathogenic criteria are met. The variant is absent from ClinVar, has no published functional data, no de novo reports, no segregation data, and no case-control evidence. SpliceAI predicts no splice impact (max delta = 0.04). OncoKB shows Unknown Oncogenic Effect. No cancerhotspots.org hotspot at this residue. No benign criteria are met.

Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), PVS1 (very strong) with only one supporting criterion (PM2) does not formally reach the Likely Pathogenic threshold (requires 1 very strong + 1 moderate, or 1 strong + 1-2 moderate, etc.). However, a frameshift variant in a known tumor suppressor gene, absent from all population databases, is strongly indicative of pathogenicity. Many clinical laboratories would classify this as Likely Pathogenic using professional judgment. Formal classification under the strict combination rules is Variant of Uncertain Significance (VUS).

Met · 2

PVS1 Very strongNM_002691.4:c.2716_2717del is a frameshift variant in exon 21 of 27 coding exons, predicted to cause a premature termination codon (NP_002682.2:p.(Arg906AspfsTer47)) subject to nonsense-mediated decay. POLD1 loss of function is an established germline disease mechanism supported by literature evidence for polymerase proofreading-associated polyposis (PPAP) and cancer predisposition. The variant meets PVS1 at full strength under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Frameshift variant (2bp deletion) causing predicted NMD in a gene where LoF is an established disease mechanism
  • POLD1 germline LoF is associated with polymerase proofreading-associated polyposis and cancer predisposition per supporting literature
  • NM_002691.4 is MANE Select transcript
  • exon 21 of 27
  • PTC in exon 22 with >365bp to last exon-exon junction
  • NMD predicted
  • Assessed under ClinGen SVI PVS1 recommendations (PMC6185798)
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingNM_002691.4:c.2716_2717del is completely absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0.00%), far below the generic ACMG PM2 threshold of <0.1%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (genomes + exomes)
  • Absent from gnomAD-Canada v1.0 (genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 19 · evaluated, threshold not reached

PS2 No de novo data are available for this variant. No publications or ClinVar submissions report de novo occurrence. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PS3 No variant-specific functional data are available. OncoKB classifies this variant as Unknown Oncogenic Effect. No publications with functional characterization of NM_002691.4:c.2716_2717del were identified. Details ▾Hide ▴
Still missing
  • No functional studies have tested this variant
PS4 No case-control or cohort data available. The variant is absent from ClinVar (zero submissions) and has not been reported in any publication. Details ▾Hide ▴
Still missing
  • No clinical cohorts or case-control studies report this variant
PM1 The variant lies at codon 906 in the C-terminal region of POLD1, which is part of the polymerase domain. However, no variant-specific or domain-specific functional data are citeable from the case materials to confirm this region is a well-established critical functional domain without benign variation. Cancerhotspots.org shows no statistically significant hotspot at this residue. Details ▾Hide ▴
Still missing
  • No citeable evidence in case materials defining the C-terminal polymerase domain as a PM1-qualifying critical domain for this variant
PM4 PM4 applies to protein length changes from in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is a frameshift truncation, which is assessed under PVS1 rather than PM4. Details ▾Hide ▴

No further detail was recorded.

PM6 No de novo data are available. No publications or ClinVar submissions report de novo occurrence of this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data available
PP1 No segregation data are available. No family studies or co-segregation analyses have been reported for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP3 Multiple in silico tools predict no significant effect. SpliceAI predicts no splice impact (max delta score = 0.04, well below the 0.1 threshold). REVEL and BayesDel scores are unavailable (not an SNV). HCI prior not available for this gene. No in silico evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (no splice impact predicted)
  • REVEL and BayesDel not applicable (variant is a deletion
  • not SNV)
Still missing
  • Frameshift variants are not typically assessed by missense-focused in silico tools
Sources
spliceai ↗
PP4 No patient phenotype or clinical data are available in the case materials to assess phenotype specificity or fit. Details ▾Hide ▴
Still missing
  • No patient phenotype data provided
PP5 The variant is absent from ClinVar — it has not been submitted by any laboratory and has no expert panel classification. No reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Still missing
  • Variant not present in ClinVar
BA1 The variant is absent from gnomAD (allele frequency 0.00%), far below the BA1 threshold of >1%. Details ▾Hide ▴
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD (allele frequency 0.00%), far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observations in healthy adults or co-occurrence data are available. The variant is absent from population databases, precluding BS2 application. Details ▾Hide ▴
Still missing
  • No observation in controls or co-occurrence data
BS3 No functional studies demonstrating no deleterious effect are available for this variant. Details ▾Hide ▴
Still missing
  • No functional studies have tested this variant
BS4 No segregation data are available to assess lack of co-segregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 No data on co-occurrence with a known pathogenic variant in trans are available. Details ▾Hide ▴
Still missing
  • No co-occurrence data available
BP4 Multiple in silico tools predict no significant effect. SpliceAI predicts no splice impact (max delta = 0.04). However, the absence of a damaging prediction does not constitute positive evidence of a benign effect for a frameshift variant — BP4 requires positive computational evidence supporting a benign interpretation, not merely absence of pathogenic signal. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (neutral
  • no splice-altering effect predicted)
Still missing
  • No in silico tool specifically predicts benign effect for this frameshift variant
Sources
spliceai ↗
BP5 No data indicate this variant is found in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternative molecular basis data available
BP6 The variant is absent from ClinVar — no reputable source has classified it as benign. Details ▾Hide ▴
Still missing
  • Variant not present in ClinVar
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 requires the same amino acid change produced by a different nucleotide change. This variant is a 2bp deletion (frameshift), not a single nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a different missense variant at the same amino acid residue classified as pathogenic. This variant is a frameshift deletion, not a missense change. Automated PM5 candidate harvesting confirmed not applicable — no same-residue missense comparators exist. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes where missense is a common disease mechanism and benign missense variation is rare. This variant is a frameshift, not a missense. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is itself a truncating (frameshift) variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This variant is an out-of-frame (frameshift) deletion. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is a 2bp frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 (revised ACMG/AMP 2024) applies to variants with strong functional evidence functionally equivalent to established pathogenic variants. No such data exist for this variant; no related pathogenic comparator was identified. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
POLD1
Transcript
NM_002691.4
Coding (HGVS c.)
NM_002691.4:c.2716_2717del
Protein (HGVS p.)
NP_002682.2:p.(Arg906AspfsTer47)
GRCh38
chr19:50415585 CGA>C
GRCh37
chr19:50918842 CGA>C

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 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -71 bp
0.010
SpliceAI acceptor gainat -221 bp
0.010
SpliceAI donor lossat -26 bp
0.040
SpliceAI donor gainat -3 bp
0.010
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.160

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Multiple in silico tools predict no significant effect. SpliceAI predicts no splice impact (max delta score = 0.04, well below the 0.1 threshold). REVEL and BayesDel scores are unavailable (not an SNV). HCI prior not available for this gene. No in silico evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (no splice impact predicted)
  • REVEL and BayesDel not applicable (variant is a deletion
  • not SNV)
Still missing
  • Frameshift variants are not typically assessed by missense-focused in silico tools
Sources
spliceai ↗
BP4 Multiple in silico tools predict no significant effect. SpliceAI predicts no splice impact (max delta = 0.04). However, the absence of a damaging prediction does not constitute positive evidence of a benign effect for a frameshift variant — BP4 requires positive computational evidence supporting a benign interpretation, not merely absence of pathogenic signal. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (neutral
  • no splice-altering effect predicted)
Still missing
  • No in silico tool specifically predicts benign effect for this frameshift variant
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This variant is a 2bp frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

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 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.040 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

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.