NM_002691.4:c.2716_2717del (p.Arg906AspfsTer47) is a frameshift null variant in POLD1, a gene in which loss of function is an established mechanism for polymerase proofreading-associated polyposis and cancer predisposition.1 Under the ClinGen SVI PVS1 decision framework (PMC6185798), this frameshift deletion meets PVS1 at very strong strength: it is predicted to undergo nonsense-mediated decay (PTC in exon 23 of 27), affects the MANE Select transcript, and is absent from population databases.2 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles), meeting PM2 at moderate strength under non-VCEP population frequency thresholds (AF < 0.1%).3 This variant is absent from ClinVar with no prior classifications or submissions. No variant-specific functional studies, case-control data, segregation data, or de novo reports were identified in the literature.4 Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one very strong criterion (PVS1) plus one moderate criterion (PM2) yields a classification of Likely Pathogenic.5
POLD1
Final classification
Likely Pathogenic
POLD1 c.2716_2717del · p.Arg906AspfsTer47
POLD1
NM_002691.4:c.2716_2717del (p.Arg906AspfsTer47) is a frameshift null variant in POLD1, a gene in which loss of function is an established mechanism for polymerase proofreading-associated polyposis and cancer predisposition.
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 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
POLD1 c.2716_2717del
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
5
generic_acmg_combination_rules
Gene diagram
· NM_002691.4 · variants mapped to exon structure
POLD1
NM_002691.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_002691.4:c.2716_2717del is a frameshift deletion in exon 21 of 27, predicted to cause a premature termination codon (p.Arg906AspfsTer47) in exon 23 that triggers nonsense-mediated decay. POLD1 loss of function is an established germline disease mechanism for polymerase proofreading-associated polyposis (PPAP) and cancer predisposition. Under the ClinGen SVI PVS1 framework (PMC6185798), this null variant meets PVS1 at full strength.
Frameshift deletion producing p.Arg906AspfsTer47 with predicted NMDPOLD1 germline LoF mechanism supported by literature (PPAPcancer predisposition)
✓
PM2
moderate
Pathogenic
NM_002691.4:c.2716_2717del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under non-VCEP gnomAD cutoffs, an allele frequency below 0.1% in all population databases supports PM2 at moderate strength.
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
Assessed · not applied
Pathogenic
PS2
No de novo data are available.
PS3
No variant-specific functional studies were identified.
PS4
No case-control or statistical enrichment data are available.
PM1
Although the variant truncates the C-terminal domain of POLD1, no domain-level functional characterization is available in the case materials to support PM1 application.
PM6
PM6 applies to assumed de novo events without confirmation of paternity and maternity.
PP1
No segregation data are available.
PP3
PP3 requires multiple lines of computational evidence supporting a deleterious effect.
PP4
No patient phenotype or family history data are available in the case materials to assess whether the clinical presentation is highly specific for POLD1-related disease.
PP5
No reputable source has reported NM_002691.4:c.2716_2717del as pathogenic.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No observations of this variant in healthy adults are documented.
BS3
No functional studies demonstrating a benign effect are available.
BS4
No segregation data are available to demonstrate lack of segregation with disease.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on gene product.
BP5
BP5 applies when a variant is found in a case with an alternate molecular basis for disease.
BP6
No reputable source has reported NM_002691.4:c.2716_2717del as benign.
N/A · 9
PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP2 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.
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.
Sources & reference links