LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-18
Case ID: NM_002691.4_c.3205G_A_20260918_221226
Framework: ACMG/AMP 2015
Variant classification summary

NM_002691.4:c.3205G>A

POLD1  · NP_002682.2:p.(Val1069Ile)  · NM_002691.4
GRCh37: chr19:50920513 G>A  ·  GRCh38: chr19:50417256 G>A
Gene: POLD1 Transcript: NM_002691.4
Final call
VUS
PM2 supporting BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
POLD1
Transcript
NM_002691.4
Protein
NP_002682.2:p.(Val1069Ile)
gnomAD AF
3.758965131839437e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS framework basis: no ClinGen VCEP/CSPEC or local POLD1 framework exists, so the generic ACMG/AMP 2015 combination rules were applied to the adjudicated criteria.
2
PM2 supporting met: gnomAD v4.1 AF 3.76e-06 with popmax 3.02e-05 is far below the 1e-4 rare-variant cutoff.
3
BP4 supporting met: missense variant with REVEL 0.197, at or below the <=0.29 tolerated threshold.
4
PS1 not met: the identical p.Val1069Ile change is only Uncertain significance (2 labs) or Likely benign (1 lab) in ClinVar, never pathogenic.
5
PS3 and BS3 not assessed: no functional assay of POLD1 p.Val1069Ile exists in the indexed literature or any curated database.
6
PS4 not met: no case-control, cohort or penetrance enrichment data for this variant exists.
7
PM1 not met: codon 1069 is not a hotspot and sits in the C-terminal CysB region, outside the cancer-critical exonuclease domain.
8
PM5 not met: the only alternate change at residue 1069, p.Val1069Asp, is Uncertain significance in ClinVar.
9
PP3 not met: REVEL 0.197 is below the >=0.644 supporting threshold for a damaging effect.
10
PP5 and BP6 not met: ClinVar VCV000537093 has zero expert-panel submissions, only conflicting single-submitter records.
11
BA1, BS1 and BS2 not met: frequency is far below 0.05/0.01 thresholds, with no homozygotes or phenotyped healthy carriers.
12
PS2, PM6, PP1, BS4 and PP4 not assessed; PM3, PM4, PVS1, BP3, BP7 not applicable; PP2, BP1, BP2 and BP5 not met - none contribute evidence.
Final determination: One supporting pathogenic criterion (PM2) plus one supporting benign criterion (BP4) meets none of the generic ACMG/AMP 2015 pathogenic, likely pathogenic, benign or likely benign combination thresholds, so the variant is classified as Variant of Uncertain Significance.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002691.4:c.3205G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Val1069Ile). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: the identical p.Val1069Ile change is classified only Uncertain significance (2 labs) or Likely benign (1 lab) in ClinVar, never pathogenic.
clinvar PMID:25394175
PS2 Not assessed Not assessed: this record contains no proband, trio, or parental-testing data, so a confirmed de novo occurrence of c.3205G>A cannot be established.
clinvar generic_acmg_combination_rules final_classification_framework PMID:25394175
PS3 Not assessed Not assessed: no functional study of POLD1 p.Val1069Ile exists - PubMed/PMC searches for V1069I, Val1069Ile and c.3205G>A returned zero records.
oncokb clinvar PMID:25394175 pvs1_gene_context generic_acmg_combination_rules
PS4 Not met Not met: no case-control or cohort enrichment data exists for p.Val1069Ile, and the only triaged paper (PMID:25394175) never mentions POLD1.
clinvar PMID:25394175
PM1 Not met Not met: codon 1069 is not a hotspot and sits in the C-terminal CysB region, outside POLD1's established cancer-critical exonuclease domain.
final_classification_framework clinvar oncokb pvs1_gene_context
PM2 Met Met at supporting strength: gnomAD v4.1 frequency 3.76e-06 with grpmax FAF 1.25e-06 and popmax 3.02e-05 falls below the 1e-4 PM2 threshold.
gnomad_v2 gnomad_v4 gnomad_canada clinvar generic_acmg_combination_rules
PM3 N/A Not applicable: POLD1 disease is dominantly inherited, so PM3's recessive disorder with a pathogenic variant in trans premise cannot be satisfied.
generic_acmg_combination_rules clinvar
PM4 N/A PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002691.4:c.3205G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Val1069Ile). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not met Not met: the only alternate change at residue 1069, p.Val1069Asp, is classified Uncertain significance in ClinVar, so no pathogenic comparator exists.
clinvar pm5_candidates PMID:25394175
PM6 Not assessed Not assessed: no proband or parental data is present in this record, so an assumed de novo occurrence of c.3205G>A cannot be asserted.
clinvar generic_acmg_combination_rules final_classification_framework PMID:25394175
PP1 Not assessed Not assessed: no pedigree or relative genotypes exist for this case, so co-segregation of c.3205G>A cannot be counted across any meioses.
clinvar generic_acmg_combination_rules final_classification_framework PMID:25394175
PP2 Not met Not met: gnomAD v4 shows POLD1 is not missense-constrained (o/e 0.84, missense Z 2.75 versus the 3.09 threshold), so benign missense variation is not rare.
gnomad_v4 oncokb pvs1_gene_context clinvar
PP3 Not met Not met: missense variant, REVEL 0.197 is below the >=0.644 PP3 supporting threshold.
revel
PP4 Not assessed Not assessed: no proband phenotype or family history is available, and the ClinVar condition labels are broad cancer-predisposition categories, not a single-gene-specific phenotype.
clinvar
PP5 Not met Not met: ClinVar VCV000537093 has zero expert-panel submissions, only conflicting single-submitter records (two uncertain significance, one likely benign), so the expert-panel requirement fails.
clinvar PMID:25394175
BA1 Not met Not met: the highest observed population frequency, 3.02e-05 in gnomAD v2.1 Admixed Americans, is over three orders of magnitude below the 0.05 BA1 threshold.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1 Not met Not met: the highest observed allele frequency, 3.02e-05, sits about 300-fold below the 0.01 BS1 threshold and no gene-specific threshold was derivable.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2 Not met Not met: zero homozygotes among 1,596,184 gnomAD v4.1 alleles and no phenotyped healthy adult carriers, and the gene's adult-onset incomplete penetrance defeats the BS2 premise.
gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS3 Not assessed Not assessed: zero PubMed/PMC records exist for POLD1 p.Val1069Ile (V1069I, Val1069Ile, c.3205G>A), so no assay can show a non-damaging effect.
oncokb clinvar PMID:25394175 pvs1_gene_context generic_acmg_combination_rules
BS4 Not assessed Not assessed: no family genotype data exists in this record, so non-segregation of c.3205G>A with disease cannot be demonstrated.
clinvar generic_acmg_combination_rules final_classification_framework PMID:25394175
BP1 Not met Not met: POLD1 disease is caused by missense variants (exonuclease-domain polyposis; CysB-region MDPL and immunodeficiency), not primarily by truncating variants.
oncokb pvs1_gene_context clinvar
BP2 Not met Not met: no pathogenic POLD1 variant was observed in cis or trans with p.Val1069Ile in any ClinVar submission or literature source examined.
generic_acmg_combination_rules clinvar gnomad_v2 gnomad_v4 gnomad_canada
BP3 N/A BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002691.4:c.3205G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Val1069Ile). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Met Met at supporting strength: REVEL 0.197 is at or below the <=0.29 BP4 threshold.
revel
BP5 Not assessed Not assessed: no proband-level genetic data or case report exists to show, or exclude, an alternate molecular basis for disease in a carrier of p.Val1069Ile.
BP6 Not met Not met: the only benign-direction ClinVar record is a single non-expert Ambry Genetics Likely benign submission (expert_panel_submissions = 0), which cannot trigger BP6.
clinvar
BP7 N/A BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002691.4:c.3205G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Val1069Ile). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
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