0%
POLD1c.927C>TUncertain significance
Print report
Variant interpretation report

POLD1 c.927C>T, p.(Pro309=)

NM_002691.4:c.927C>T NP_002682.2:p.(Pro309=) Synonymous · exon 8 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

POLD1 encodes the catalytic subunit of DNA polymerase delta, an enzyme that carries both DNA synthesis and proofreading (3' to 5' exonuclease) activities and is essential for accurate DNA replication and repair. Germline mutations in its exonuclease domain cause polyposis and predispose people to colorectal, endometrial, and possibly brain cancers. In cancer, POLD1 defects impair replication fidelity, leading to the accumulation of many mutations (an ultra-mutated phenotype) that may make tumors more responsive to immunotherapy, though somatic POLD1 mutations are rare.

NCBI Gene ↗ OncoKB ↗
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Met (supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: the sole met criterion is PM2 (supporting) - absence from gnomAD v2.1, v4.1, and gnomAD-Canada - which alone meets no pathogenic or benign combination threshold.

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.

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 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.

28 criteria with recorded statuses: 1 met · 2 not met · 17 not assessed · 8 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

Population evidence is limited to absence from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

This supports PM2 at supporting strength under the generic ACMG/AMP fallback; BA1 and BS1 are not met because no elevated allele frequency was observed, and BS2 is not assessed because no healthy homozygote/hemizygote evidence is available.

Met · 1

PM2 SupportingMet (supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Details ▾Hide ▴
Reasoning

NM_002691.4:c.927C>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. With no applicable POLD1-specific population rule, this supports PM2 at the generic supporting level.

Rule
Generic ACMG/AMP PM2: variant absent from or extremely rare in population databases appropriate to the tested ancestry and disease context; applied here as supporting evidence because the variant was absent from all three queried resources.
Evidence considered
  • The gnomAD v2.1 query for 19-50905955-C-T returned search_status=absent.
  • The gnomAD v4.1 query for 19-50402698-C-T returned search_status=absent.
  • The gnomAD-Canada v1.0 query for 19-50402698-C-T returned search_status=absent.
  • The variant is classified in the bundle as synonymous, NM_002691.4:c.927C>T; no population frequency or homozygote observation was reported.
  • No applicable POLD1 VCEP/CSPEC framework was retrieved, so generic ACMG/AMP PM2 was applied.
Still missing
  • The case bundle does not provide explicit allele-number, coverage, or ancestry-specific sensitivity metrics for the three population datasets.
  • No POLD1-specific VCEP/CSPEC PM2 rule was available.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 2 · evaluated, threshold not reached

BA1 Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >5% stand-alone benign threshold. Details ▾Hide ▴
Reasoning

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore no allele frequency exceeds a stand-alone benign threshold of >5%.

Rule
Generic ACMG/AMP BA1 requires an allele frequency high enough to be stand-alone benign evidence; no such frequency is present because the variant was absent from all queried population datasets.
Evidence considered
  • The normalized variant is NM_002691.4:c.927C>T, corresponding to NC_000019.9:g.50905955C>T and NC_000019.10:g.50402698C>T.
  • The gnomAD v2.1 query returned search_status=absent and the evidence sentence states: Absent from gnomAD v2.1.
  • The gnomAD v4.1 query returned search_status=absent and the evidence sentence states: Absent from gnomAD v4.1.
  • The gnomAD-Canada v1.0 query returned search_status=absent and the evidence sentence states: Absent from gnomAD-Canada v1.0.
  • No applicable POLD1 VCEP/CSPEC framework was retrieved; generic ACMG/AMP fallback was therefore used.
Still missing
  • The case bundle does not provide explicit dataset allele-number or coverage metrics, although each queried population resource returned an absent result.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with no frequency above a benign threshold. Details ▾Hide ▴
Reasoning

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. No population frequency above a disease-specific benign threshold is available, so BS1 is not met.

Rule
Generic ACMG/AMP BS1 requires a population frequency greater than expected for the disorder; absence from the queried population resources does not satisfy this benign criterion.
Evidence considered
  • The gnomAD v2.1 query returned search_status=absent.
  • The gnomAD v4.1 query returned search_status=absent.
  • The gnomAD-Canada v1.0 query returned search_status=absent.
  • No POLD1-specific VCEP frequency threshold was available, and no disease prevalence/penetrance threshold calculation was supplied in the case bundle.
  • No frequency observation was found that could support BS1.
Still missing
  • The case bundle does not provide an explicit POLD1 disease prevalence/penetrance-derived maximum credible allele frequency or dataset allele-number details.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not assessed · 17 · no assessment recorded

PS2 Not assessed: no de novo evidence (proband/parent genotypes or parental testing) was available. Details ▾Hide ▴
Reasoning

No proband-specific de novo evidence is available. The case-evidence bundle contains no affected proband/parent genotypes, parental testing results, maternity/paternity confirmation, or information excluding parental mosaicism; therefore PS2 cannot be assessed.

Rule
Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no evidence of parental mosaicism; maternity and paternity confirmed where applicable. No applicable POLD1 VCEP/CSPEC framework was retrieved.
Evidence considered
  • The consolidated case-evidence bundle reports no case-level family segregation or parental-testing data.
  • No literature paper was identified or extracted for this variant or for a relevant de novo observation.
Still missing
  • Document the proband genotype and phenotype.
  • Provide validated maternal and paternal testing showing the variant is absent in both biologic parents.
  • Provide maternity/paternity confirmation and assess the possibility of parental mosaicism.
PS3 Not assessed: no validated functional assay evidence for this variant was available. Details ▾Hide ▴
Reasoning

No validated functional assay evidence for NM_002691.4:c.927C>T (POLD1 p.Pro309=) was identified in the consolidated case-evidence bundle. The bundle contains no relevant publications, paper extracts, or assay results with experimental controls and biological relevance sufficient to assess PS3.

Evidence considered
  • The governing framework retrieval found no applicable POLD1-specific VCEP/CSPEC; generic ACMG/AMP fallback therefore applies.
  • The consolidated case-evidence bundle reports zero literature PMIDs and contains empty fulltext_map.json and paper_extracts.json.
  • The bundle contains no variant-specific functional assay, assay-control, or experimental-result evidence for NM_002691.4:c.927C>T.
Still missing
  • A validated assay directly evaluating the variant's effect on POLD1 function is unavailable.
  • Assay controls, replication, quantitative effect size, and biological relevance cannot be evaluated.
PS4 Not assessed: no case-control or affected-case enrichment data for this exact variant were available. Details ▾Hide ▴
Reasoning

No case-control cohort, affected-case series, or other enrichment data for the exact variant were retrieved; PS4 cannot be assessed.

Rule
Generic ACMG/AMP PS4 requires statistically increased prevalence in affected individuals compared with controls.
Evidence considered
  • The consolidated literature pass contains no PMID or variant-specific publication for NM_002691.4:c.927C>T (POLD1 p.Pro309=).
Still missing
  • Variant-specific case and control counts or a published case-control enrichment analysis are needed.
PM3 Not assessed: no data establishing this variant in trans with a pathogenic variant were available. Details ▾Hide ▴
Reasoning

No applicable POLD1 VCEP or gene-specific framework was available, so the generic ACMG/AMP framework was used. The case bundle contains no affected-proband observations, additional pathogenic/likely pathogenic variants, phase information, parental testing, or inheritance data establishing this variant in trans with a pathogenic variant. PM3 therefore cannot be assessed.

Rule
Generic ACMG/AMP 2015 PM3: apply when a variant is observed in trans with a pathogenic variant in an affected individual with a recessive disorder, with strength determined by validated specifications; the required affected-proband and phase evidence is absent here.
Evidence considered
  • The case bundle identifies POLD1 and NM_002691.4:c.927C>T (NP_002682.2:p.(Pro309=)) but provides no allelic or family segregation evidence.
  • The case bundle reports no retrieved literature PMIDs and an empty paper_extracts object; no publication was available for evaluation of PM3.
  • No POLD1 CSPEC/VCEP framework was retrieved; generic ACMG/AMP fallback was therefore used.
Still missing
  • Affected-proband or family-level clinical observations are not provided.
  • No second pathogenic or likely pathogenic allele is documented.
  • Phase and parental inheritance testing are not documented.
  • The relevant disease inheritance mode is not established in the case bundle.
PM6 Not assessed: no presumed de novo observation with parental testing was available. Details ▾Hide ▴
Reasoning

No presumed de novo observation is available. The bundle provides no affected proband/parent genotypes, parental testing, or evidence supporting de novo origin without confirmed maternity and paternity; therefore PM6 cannot be assessed.

Rule
Generic ACMG/AMP PM6: presumed de novo occurrence in a patient with the disease, without confirmation of maternity and paternity. No applicable POLD1 VCEP/CSPEC framework was retrieved.
Evidence considered
  • The consolidated case-evidence bundle contains no presumed de novo case description or parental genotype data.
  • No literature paper was identified or extracted for this variant or for a relevant de novo observation.
Still missing
  • Provide a documented presumed de novo case with the proband genotype and relevant phenotype.
  • Provide parental testing or other evidence establishing that the variant was not inherited.
  • Confirm or otherwise address maternity and paternity and parental mosaicism.
PP1 Not assessed: no segregation data (informative relatives or meioses) were available. Details ▾Hide ▴
Reasoning

No segregation data are available. The bundle does not identify informative affected or unaffected relatives, the number of informative meioses, genotype-phenotype concordance, or a POLD1-specific segregation threshold; therefore PP1 cannot be assessed.

Rule
Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members in a gene known to cause the disease; strength depends on the amount and informativeness of segregation. No applicable POLD1 VCEP/CSPEC framework was retrieved.
Evidence considered
  • The consolidated case-evidence bundle contains no family pedigree, relative genotypes, meioses count, or segregation observations.
  • No literature paper was identified or extracted for informative segregation of this variant.
Still missing
  • Provide a pedigree with phenotypes and genotypes for informative relatives.
  • Document the number of informative meioses and whether the variant co-segregates with the relevant phenotype.
  • Apply an applicable POLD1-specific or otherwise justified segregation threshold if sufficient families are available.
PP3 Not assessed: SpliceAI max delta 0.00 predicts no splice impact, but no verified threshold publication was available to apply it. Details ▾Hide ▴
Reasoning

POLD1 NM_002691.4:c.927C>T is synonymous (p.Pro309=), so the splice-prediction path is the applicable PP3/BP4 mechanism. SpliceAI reports a maximum delta score of 0.00, which does not predict splice disruption. However, no verified publication and PMID establishing a PP3 decision threshold for this SpliceAI use are present in the case sources; therefore PP3 is not assessed rather than inferred from an uncited cutoff.

Rule
generic_non_missense_splice_path; calibrated_threshold_not_verified
Evidence considered
  • The normalized consequence is synonymous, NP_002682.2:p.(Pro309=), so missense-only REVEL/BayesDel evidence is not applicable.
  • SpliceAI Lookup reports max delta score 0.00 for NM_002691.4:c.927C>T, with no significant predicted splice impact.
  • The generic fallback names SpliceAI decision ranges but attributes them only to 'Walker et al. 2023' without a verifiable PMID in the supplied case evidence; under the required calibration rule, this is insufficient to use a numerical predictor cutoff.
Still missing
  • A verified, published SpliceAI PP3 calibration with its PMID and applicable decision threshold is needed before this predictor can be used for PP3.
Sources
spliceai ↗generic_acmg_combination_rules
PP4 Not assessed: no phenotype or clinical indication data were available to evaluate specificity. Details ▾Hide ▴
Reasoning

No phenotype, clinical indication, segregation context, or variant-specific affected-case report was retrieved; phenotype specificity cannot be evaluated.

Rule
Generic ACMG/AMP PP4 requires a patient phenotype or family history highly specific for a disease with a single genetic etiology.
Evidence considered
  • The consolidated case evidence contains no patient phenotype or variant-specific literature for NM_002691.4:c.927C>T.
Still missing
  • A documented proband phenotype and evidence that it is highly specific for a POLD1-associated disorder are needed.
PP5 Not assessed: the exact variant is absent from ClinVar, so no expert-panel assertion exists. Details ▾Hide ▴
Reasoning

The exact variant is absent from ClinVar; therefore no exact-variant pathogenic or likely pathogenic ClinVar expert-panel assertion is available.

Rule
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion.
Evidence considered
  • ClinVar exact-variant search for NM_002691.4:c.927C>T returned no result.
Still missing
  • An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is required.
Sources
clinvar ↗
BS2 Not assessed: no evidence of unaffected adult homozygotes or hemizygotes was available. Details ▾Hide ▴
Reasoning

No evidence of unaffected adult homozygotes or, where applicable, hemizygotes was provided. Absence of a variant record in population databases cannot establish the BS2 observation requirement.

Rule
Generic ACMG/AMP BS2 requires observation of the variant in healthy adults in the homozygous state, or in hemizygous state for an X-linked disorder when applicable; this evidence is unavailable.
Evidence considered
  • The queried gnomAD resources reported the variant as absent rather than reporting unaffected homozygote observations.
  • The case bundle contains no homozygote or hemizygote evidence and no unaffected-adult phenotype assessment.
Still missing
  • No homozygote/hemizygote count or individual-level population observation was available.
  • No adequately phenotyped unaffected-adult cohort was identified in the case bundle.
BS3 Not assessed: no validated functional assay evidence of a normal (benign) effect was available. Details ▾Hide ▴
Reasoning

No validated functional assay evidence demonstrating a normal or benign effect of NM_002691.4:c.927C>T (POLD1 p.Pro309=) was identified in the consolidated case-evidence bundle. The available data do not establish assay validity, appropriate controls, reproducibility, or relevance to POLD1 biology, so BS3 cannot be assessed.

Evidence considered
  • The governing framework retrieval found no applicable POLD1-specific VCEP/CSPEC; generic ACMG/AMP fallback therefore applies.
  • The consolidated case-evidence bundle reports zero literature PMIDs and contains empty fulltext_map.json and paper_extracts.json.
  • The bundle contains no variant-specific functional assay, assay-control, or experimental-result evidence for NM_002691.4:c.927C>T.
Still missing
  • A validated assay directly evaluating the variant's effect on POLD1 function is unavailable.
  • Evidence for a normal functional result with suitable controls and biologically relevant readout is unavailable.
BS4 Not assessed: no non-segregation evidence (unaffected relatives tested) was available. Details ▾Hide ▴
Reasoning

No non-segregation evidence is available. The bundle contains no unaffected relatives tested for the variant, no informative meioses showing absence in affected relatives, and no phenotype assessment sufficient to evaluate BS4; therefore BS4 cannot be assessed.

Rule
Generic ACMG/AMP BS4: lack of segregation in affected members of a family; interpretation requires informative affected relatives and consideration of phenocopies, reduced penetrance, and variable expressivity. No applicable POLD1 VCEP/CSPEC framework was retrieved.
Evidence considered
  • The consolidated case-evidence bundle contains no family pedigree, relative genotypes, or non-segregation observations.
  • No literature paper was identified or extracted for non-segregation of this variant.
Still missing
  • Provide genotypes and reliable phenotype assessments for informative affected and unaffected relatives.
  • Document informative non-segregation observations and the number of meioses tested.
  • Consider age-dependent penetrance, phenocopies, and variable expressivity before applying BS4.
BP2 Not assessed: no observation of the variant in trans or in cis with a pathogenic variant was available. Details ▾Hide ▴
Reasoning

No applicable POLD1 VCEP or gene-specific framework was available, so the generic ACMG/AMP framework was used. The case bundle contains no observation of this variant in trans with a pathogenic variant in a recessive disorder and no observation in cis with a pathogenic variant. BP2 therefore cannot be assessed.

Rule
Generic ACMG/AMP 2015 BP2: apply when a variant is observed in trans with a pathogenic variant in a recessive disorder or in cis with a pathogenic variant; neither required observation nor phase evidence is present here.
Evidence considered
  • The case bundle identifies POLD1 and NM_002691.4:c.927C>T (NP_002682.2:p.(Pro309=)) but provides no allelic, phase, or segregation evidence.
  • The case bundle reports no retrieved literature PMIDs and an empty paper_extracts object; no publication was available for evaluation of BP2.
  • No POLD1 CSPEC/VCEP framework was retrieved; generic ACMG/AMP fallback was therefore used.
Still missing
  • No affected individual or family genotype data are provided.
  • No pathogenic or likely pathogenic comparator allele is documented.
  • No phase determination (cis or trans) is documented.
  • The relevant disease inheritance mode is not established in the case bundle.
BP4 Not assessed: SpliceAI max delta 0.00 suggests no splice impact, but no verified threshold publication was available to apply BP4. Details ▾Hide ▴
Reasoning

POLD1 NM_002691.4:c.927C>T is a synonymous variant and SpliceAI reports a maximum delta score of 0.00, consistent with no predicted splice impact. BP4 is nevertheless not assessed because the supplied case evidence does not provide a verified publication and PMID for the SpliceAI benign-supporting decision threshold; an unverified numerical cutoff cannot be used.

Rule
generic_non_missense_splice_path; calibrated_threshold_not_verified
Evidence considered
  • The normalized consequence is synonymous, NP_002682.2:p.(Pro309=), so the non-missense splice-prediction path is applicable and REVEL/BayesDel are not applicable.
  • SpliceAI Lookup reports max delta score 0.00 for NM_002691.4:c.927C>T, with no significant predicted splice impact.
  • The generic fallback names SpliceAI decision ranges but attributes them only to 'Walker et al. 2023' without a verifiable PMID in the supplied case evidence; under the required calibration rule, this is insufficient to use a numerical predictor cutoff.
Still missing
  • A verified, published SpliceAI BP4 calibration with its PMID and applicable decision threshold is needed before this predictor can support BP4.
Sources
spliceai ↗generic_acmg_combination_rules
BP5 Not assessed: no affected individual with an alternative molecular diagnosis explaining the phenotype was found. Details ▾Hide ▴
Reasoning

No affected individual carrying this variant and an alternative molecular diagnosis that fully explains a POLD1-relevant phenotype was retrieved.

Rule
Generic ACMG/AMP BP5 requires an alternate molecular basis for disease in an affected individual carrying the variant.
Evidence considered
  • No variant-specific case reports or phenotype records were available in the consolidated evidence bundle.
Still missing
  • A variant-specific affected case with a confirmed alternative molecular diagnosis that fully explains the phenotype is needed.
BP6 Not assessed: the exact variant is absent from ClinVar, so no benign expert-panel assertion exists. Details ▾Hide ▴
Reasoning

The exact variant is absent from ClinVar; therefore no exact-variant benign or likely benign ClinVar expert-panel assertion is available.

Rule
Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign assertion.
Evidence considered
  • ClinVar exact-variant search for NM_002691.4:c.927C>T returned no result.
Still missing
  • An exact-variant ClinVar expert-panel Benign or Likely benign classification is required.
Sources
clinvar ↗
BP7 Not assessed: no nucleotide conservation evidence or gene-specific BP7 specification was available. Details ▾Hide ▴
Reasoning

The variant is synonymous (p.Pro309=) and SpliceAI predicts no significant splice impact, satisfying only part of the generic BP7 evidence concept. No nucleotide conservation evidence or applicable POLD1 VCEP BP7 specification is supplied, so BP7 cannot be assessed.

Rule
generic_BP7_requires_synonymous_no_splice_effect_and_nonconserved_nucleotide
Evidence considered
  • The normalized consequence is synonymous, NP_002682.2:p.(Pro309=).
  • SpliceAI Lookup reports max delta score 0.00 for NM_002691.4:c.927C>T, with no significant predicted splice impact.
  • No POLD1 CSPEC/VCEP material was retrieved, and the case bundle supplies no nucleotide-conservation result for c.927.
Still missing
  • Provide a validated nucleotide-conservation assessment for c.927 or an applicable POLD1 VCEP BP7 rule.
Sources
spliceai ↗generic_acmg_combination_rules
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: as a synonymous change, no null-variant mechanism (nonsense-mediated decay, truncation, or splice disruption) applies. Details ▾Hide ▴
Reasoning

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.927C>T in POLD1 is a synonymous (silent) substitution predicted to produce NP_002682.2:p.(Pro309=). 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.

Rule
deterministic_prefilter: requires_null_variant_class
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PS1 N/ANot applicable: synonymous (p.Pro309=), so no altered amino acid exists to compare against a previously pathogenic variant. Details ▾Hide ▴
Reasoning

PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_002691.4:c.927C>T in POLD1 is a synonymous (silent) substitution predicted to produce NP_002682.2:p.(Pro309=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM1 N/ANot applicable: synonymous variant, so no altered residue exists to evaluate for a mutational hotspot or critical domain. Details ▾Hide ▴
Reasoning

PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_002691.4:c.927C>T in POLD1 is a synonymous (silent) substitution predicted to produce NP_002682.2:p.(Pro309=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM4 N/ANot applicable: synonymous variant, so no protein length change occurs for this criterion to evaluate. Details ▾Hide ▴
Reasoning

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.927C>T in POLD1 is a synonymous (silent) substitution predicted to produce NP_002682.2:p.(Pro309=). 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.

Rule
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PM5 N/ANot applicable: no missense change exists at this residue to compare against a different pathogenic missense change. Details ▾Hide ▴
Reasoning

PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_002691.4:c.927C>T in POLD1 is a synonymous (silent) substitution predicted to produce NP_002682.2:p.(Pro309=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP2 N/ANot applicable: no missense change is present, so the gene's missense-constraint properties are irrelevant. Details ▾Hide ▴
Reasoning

PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_002691.4:c.927C>T in POLD1 is a synonymous (silent) substitution predicted to produce NP_002682.2:p.(Pro309=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP1 N/ANot applicable: no missense change is present, so the gene's truncating-variant mechanism is irrelevant. Details ▾Hide ▴
Reasoning

BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_002691.4:c.927C>T in POLD1 is a synonymous (silent) substitution predicted to produce NP_002682.2:p.(Pro309=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP3 N/ANot applicable: the variant does not alter protein length within a repetitive region. Details ▾Hide ▴
Reasoning

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.927C>T in POLD1 is a synonymous (silent) substitution predicted to produce NP_002682.2:p.(Pro309=). 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.

Rule
deterministic_prefilter: requires_repeat_region_indel
Evidence considered
  • Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules

Identifiers

Gene
POLD1
Transcript
NM_002691.4
Coding (HGVS c.)
NM_002691.4:c.927C>T
Protein (HGVS p.)
NP_002682.2:p.(Pro309=)
GRCh38
chr19:50402698 C>T
GRCh37
chr19:50905955 C>T
Location and type
Exon 8 · synonymous

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

Pangolin splice lossmagnitude shown
-0.014
Pangolin splice gain
0.017

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 Not assessed: SpliceAI max delta 0.00 predicts no splice impact, but no verified threshold publication was available to apply it. Details ▾Hide ▴
Reasoning

POLD1 NM_002691.4:c.927C>T is synonymous (p.Pro309=), so the splice-prediction path is the applicable PP3/BP4 mechanism. SpliceAI reports a maximum delta score of 0.00, which does not predict splice disruption. However, no verified publication and PMID establishing a PP3 decision threshold for this SpliceAI use are present in the case sources; therefore PP3 is not assessed rather than inferred from an uncited cutoff.

Rule
generic_non_missense_splice_path; calibrated_threshold_not_verified
Evidence considered
  • The normalized consequence is synonymous, NP_002682.2:p.(Pro309=), so missense-only REVEL/BayesDel evidence is not applicable.
  • SpliceAI Lookup reports max delta score 0.00 for NM_002691.4:c.927C>T, with no significant predicted splice impact.
  • The generic fallback names SpliceAI decision ranges but attributes them only to 'Walker et al. 2023' without a verifiable PMID in the supplied case evidence; under the required calibration rule, this is insufficient to use a numerical predictor cutoff.
Still missing
  • A verified, published SpliceAI PP3 calibration with its PMID and applicable decision threshold is needed before this predictor can be used for PP3.
Sources
spliceai ↗generic_acmg_combination_rules
BP4 Not assessed: SpliceAI max delta 0.00 suggests no splice impact, but no verified threshold publication was available to apply BP4. Details ▾Hide ▴
Reasoning

POLD1 NM_002691.4:c.927C>T is a synonymous variant and SpliceAI reports a maximum delta score of 0.00, consistent with no predicted splice impact. BP4 is nevertheless not assessed because the supplied case evidence does not provide a verified publication and PMID for the SpliceAI benign-supporting decision threshold; an unverified numerical cutoff cannot be used.

Rule
generic_non_missense_splice_path; calibrated_threshold_not_verified
Evidence considered
  • The normalized consequence is synonymous, NP_002682.2:p.(Pro309=), so the non-missense splice-prediction path is applicable and REVEL/BayesDel are not applicable.
  • SpliceAI Lookup reports max delta score 0.00 for NM_002691.4:c.927C>T, with no significant predicted splice impact.
  • The generic fallback names SpliceAI decision ranges but attributes them only to 'Walker et al. 2023' without a verifiable PMID in the supplied case evidence; under the required calibration rule, this is insufficient to use a numerical predictor cutoff.
Still missing
  • A verified, published SpliceAI BP4 calibration with its PMID and applicable decision threshold is needed before this predictor can support BP4.
Sources
spliceai ↗generic_acmg_combination_rules
BP7 Not assessed: no nucleotide conservation evidence or gene-specific BP7 specification was available. Details ▾Hide ▴
Reasoning

The variant is synonymous (p.Pro309=) and SpliceAI predicts no significant splice impact, satisfying only part of the generic BP7 evidence concept. No nucleotide conservation evidence or applicable POLD1 VCEP BP7 specification is supplied, so BP7 cannot be assessed.

Rule
generic_BP7_requires_synonymous_no_splice_effect_and_nonconserved_nucleotide
Evidence considered
  • The normalized consequence is synonymous, NP_002682.2:p.(Pro309=).
  • SpliceAI Lookup reports max delta score 0.00 for NM_002691.4:c.927C>T, with no significant predicted splice impact.
  • No POLD1 CSPEC/VCEP material was retrieved, and the case bundle supplies no nucleotide-conservation result for c.927.
Still missing
  • Provide a validated nucleotide-conservation assessment for c.927 or an applicable POLD1 VCEP BP7 rule.
Sources
spliceai ↗generic_acmg_combination_rules

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.