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POLD1c.1704G>AUncertain significance
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Variant interpretation report

POLD1 c.1704G>A, p.(Leu568=)

NM_002691.4:c.1704G>A NP_002682.2:p.(Leu568=) 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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 allele frequency threshold (<0.1%) for absence from population controls.

Benign criteria applied · 1
BP7Supporting
BP7 · supporting

NM_002691.4:c.1704G>A is a synonymous variant (p.Leu568=) for which SpliceAI predicts no splice impact (max delta score = 0.00, no acceptor gain/loss or donor gain/loss). Conservation data at this nucleotide position are not available, but the synonymous nature with no predicted splice alteration supports a benign interpretation.

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: PM2 supporting, BP7 supporting benign; combination = 1 supporting + 1 supporting benign, 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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP7 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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.

27 criteria with recorded statuses: 2 met · 5 not met · 14 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002691.4:c.1704G>A (p.Leu568=) is a synonymous variant in POLD1 exon 14 that is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2_supporting).

SpliceAI predicts no splice impact (max delta score = 0.00), and the variant is synonymous with no predicted amino acid change (BP7_supporting_benign).

This variant is absent from ClinVar and has not been reported in COSMIC. No functional studies, segregation data, or variant-specific publications were identified.

The available evidence includes one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP7). Under generic ACMG/AMP 2015 combination rules (PMID:25741868), this does not meet thresholds for Likely Pathogenic (requires ≥1 Moderate + ≥4 Supporting, or stronger), Likely Benign (requires ≥2 Supporting benign), or Benign (requires ≥2 Strong benign or BA1). The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 allele frequency threshold (<0.1%) for absence from population controls. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles).
  • Absent from gnomAD v4.1 (0 alleles).
  • Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP7 SupportingNM_002691.4:c.1704G>A is a synonymous variant (p.Leu568=) for which SpliceAI predicts no splice impact (max delta score = 0.00, no acceptor gain/loss or donor gain/loss). Conservation data at this nucleotide position are not available, but the synonymous nature with no predicted splice alteration supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Leu568=).
  • SpliceAI max delta = 0.00
  • all delta scores = 0.0 (DS_AG=0
  • DS_AL=0
  • DS_DG=0
  • DS_DL=0).
  • Pangolin splice gain = 0.0
  • splice loss = 0.0.
Still missing
  • Nucleotide-level conservation data (PhyloP
  • GERP) not available to confirm the nucleotide is not highly conserved.
Sources
spliceai ↗

Not met · 5 · evaluated, threshold not reached

PM1 This variant does not reside in a statistically significant mutational hotspot (cancerhotspots.org) and no well-established POLD1 functional domain has been specifically implicated at this residue. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org screen negative
  • residue L568 not identified as a recurrently mutated position (screenshot verified).
PP3 No computational evidence supports a deleterious effect. SpliceAI predicts no splice impact (max delta score = 0.00), and REVEL and BayesDel scores are not available for this synonymous variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no splice impact).
  • REVEL score unavailable.
  • BayesDel score unavailable.
Still missing
  • No REVEL or BayesDel scores available for this position.
Sources
spliceai ↗
BA1 This variant is absent from gnomAD; its population allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD; its population allele frequency does not exceed the 0.3% BS1 threshold for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. Only a single line (SpliceAI, max delta = 0.00) is available and applicable; REVEL and BayesDel are unavailable for this synonymous variant. BP7 is the more specific criterion for this evidence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no splice impact)
  • single computational line only.
Still missing
  • No REVEL or BayesDel scores available
  • multiple computational lines not met.
Sources
spliceai ↗

Not assessed · 14 · no assessment recorded

PS2 No de novo occurrence data (with confirmed paternity and maternity) are available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PS3 No well-established in vitro or in vivo functional studies are available for NM_002691.4:c.1704G>A. Details ▾Hide ▴
Still missing
  • No functional data available for this variant.
PS4 No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals are available. Details ▾Hide ▴
Still missing
  • No case-control studies available.
PM6 No de novo observation (without confirmation of paternity and maternity) has been reported for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports available.
PP1 No co-segregation data are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP4 No patient phenotype or family history data are available to assess specificity for a POLD1-associated disorder. Details ▾Hide ▴
Still missing
  • No phenotype data available.
PP5 No reputable source has reported this variant as pathogenic. Details ▾Hide ▴
Still missing
  • No such report identified.
BS2 No data are available regarding observation of this variant in healthy adult individuals for a fully penetrant disorder. Details ▾Hide ▴
Still missing
  • No healthy control observation data available.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant. Details ▾Hide ▴
Still missing
  • No functional data available.
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 are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
  • No trans-phase observation data available.
BP5 No data are available regarding observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data available.
BP6 No reputable source has reported this variant as benign. Details ▾Hide ▴
Still missing
  • No such report identified.
PS5 No reputable source has reported this variant as pathogenic where the underlying evidence is unavailable for independent evaluation. Details ▾Hide ▴
Still missing
  • No such report identified.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002691.4:c.1704G>A is a synonymous variant (p.Leu568=). It does not fall into the null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus) required for generic PVS1 application per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Synonymous variant with no predicted null effect on protein
  • pvs1_variant_assessment confirms apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/APS1 requires the same amino acid change as a previously established pathogenic variant. This synonymous variant produces no amino acid change (p.Leu568=), so PS1 is structurally not applicable. Details ▾Hide ▴
Evidence considered
  • Synonymous variant with no amino acid change.
PM5 N/APM5 applies to novel missense changes at a residue where a different pathogenic missense change has been reported. This synonymous variant produces no amino acid change (p.Leu568=) and therefore has no missense comparator context. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • no amino acid residue change for missense comparator analysis.
Sources
pm5_candidates
PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This variant is synonymous, not missense. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • PP2 missense-only criterion not applicable.
BP1 N/ABP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. This variant is synonymous, not missense. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • BP1 missense-only criterion not applicable.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
POLD1
Transcript
NM_002691.4
Coding (HGVS c.)
NM_002691.4:c.1704G>A
Protein (HGVS p.)
NP_002682.2:p.(Leu568=)
GRCh38
chr19:50407344 G>A
GRCh37
chr19:50910601 G>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 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 -17 bp
0.000
SpliceAI acceptor gainat -313 bp
0.000
SpliceAI donor lossat -200 bp
0.000
SpliceAI donor gainat +123 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP7 SupportingNM_002691.4:c.1704G>A is a synonymous variant (p.Leu568=) for which SpliceAI predicts no splice impact (max delta score = 0.00, no acceptor gain/loss or donor gain/loss). Conservation data at this nucleotide position are not available, but the synonymous nature with no predicted splice alteration supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • Synonymous variant (p.Leu568=).
  • SpliceAI max delta = 0.00
  • all delta scores = 0.0 (DS_AG=0
  • DS_AL=0
  • DS_DG=0
  • DS_DL=0).
  • Pangolin splice gain = 0.0
  • splice loss = 0.0.
Still missing
  • Nucleotide-level conservation data (PhyloP
  • GERP) not available to confirm the nucleotide is not highly conserved.
Sources
spliceai ↗
PP3 No computational evidence supports a deleterious effect. SpliceAI predicts no splice impact (max delta score = 0.00), and REVEL and BayesDel scores are not available for this synonymous variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no splice impact).
  • REVEL score unavailable.
  • BayesDel score unavailable.
Still missing
  • No REVEL or BayesDel scores available for this position.
Sources
spliceai ↗
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. Only a single line (SpliceAI, max delta = 0.00) is available and applicable; REVEL and BayesDel are unavailable for this synonymous variant. BP7 is the more specific criterion for this evidence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no splice impact)
  • single computational line only.
Still missing
  • No REVEL or BayesDel scores available
  • multiple computational lines not met.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 0.000 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 = 0.00).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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.