NM_002691.4:c.187G>A

POLD1 · NP_002682.2:p.(Glu63Lys) · NM_002691.4

GRCh37: chr19:50902295 G>A · GRCh38: chr19:50399038 G>A

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

BP4 moderate

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Glu63Lys)

gnomAD AF

3.151749671317534e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

BP4 (moderate, benign): REVEL 0.018 falls below the <=0.183 moderate benign cutoff for this missense variant, indicating a non-damaging protein effect.

Final determination: Generic ACMG/AMP 2015: one benign criterion at supporting/moderate strength (BP4) with no pathogenic criteria met satisfies no Benign, Likely Benign, Likely Pathogenic, or Pathogenic combination, giving 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.187G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Glu63Lys). 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 only p.Glu63Lys record in ClinVar (c.187G>A, this variant) has 0 pathogenic submissions, and no other nucleotide change yields p.Glu63Lys.	clinvar
PS2	Not assessed	Not assessed: no de novo observation or parental testing for POLD1 c.187G>A exists in the ClinVar record 407981 or any retrieved source.	clinvar final_classification_framework generic_acmg_combination_rules
PS3	Not met	Not met: no functional assay for POLD1 p.Glu63Lys exists in any source, and OncoKB returned no variant-specific functional evidence (variant not reviewed).	oncokb PMID:26467025 PMID:25394175 generic_acmg_combination_rules
PS4	Not met	Not met: no odds ratio or case-control enrichment was reported for this variant, which instead appears in gnomAD non-cancer controls at 6.746e-05 (13/192,696 alleles).	clinvar gnomad_v2 PMID:25394175 PMID:26467025
PM1	Not met	Not met: Glu63 sits outside POLD1's exonuclease (243-477) and polymerase (541-973) domains and is not a reported hotspot (Cancer Hotspots: no row).	oncokb
PM2	Not met	Not met: the population-maximum filtering frequency is 2.90e-04 (Admixed American 4.30e-04) in gnomAD v4.1, exceeding the 0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not met	Not met: POLD1-related disease is dominant, and no POLD1 variant in trans with c.187G>A is reported; gnomAD v4.1 shows 0 homozygotes among 1,554,692 alleles.	clinvar gnomad_v2 gnomad_v4 oncokb pvs1_gene_context generic_acmg_combination_rules PMID:26467025 PMID:25394175
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.187G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Glu63Lys). 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: all three alternative codon-63 missense variants in ClinVar (Glu63Gln, Glu63Ala, Glu63Asp) are Uncertain significance or Likely benign, none pathogenic.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no assumed de novo occurrence of POLD1 c.187G>A is reported in any source, and no parental data exist to support one.	clinvar final_classification_framework generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no pedigree, affected-relative genotypes or informative meioses are reported for POLD1 c.187G>A in any available source.	clinvar final_classification_framework generic_acmg_combination_rules
PP2	Not met	Not met: POLD1 gnomAD missense constraint (mis_z 2.75, o/e missense 0.84) is near neutral and does not establish a low rate of benign missense variation.	gnomad_v4 oncokb
PP3	Not met	Not met: REVEL 0.018 is far below the >=0.644 supporting PP3 threshold for this POLD1 missense variant.	revel
PP4	Not assessed	Not assessed: no proband phenotype, HPO terms, or family history is available; general POLD1 cancer context cannot establish phenotype specificity.	clinvar
PP5	Not met	Not met: the exact-variant ClinVar record (VCV000407981) has zero expert-panel submissions and only single-submitter laboratory classifications (1 star, conflicting).	clinvar
BA1	Not met	Not met: the highest ancestry frequency is 4.30e-04 in Admixed American individuals (gnomAD v4.1), far below the 0.05 BA1 stand-alone threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the top ancestry frequency is 4.30e-04 in Admixed American individuals (gnomAD v4.1), over 20-fold below the 0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: zero homozygotes in gnomAD v2.1, v4.1 and both non-cancer subsets, and no healthy-adult observation for this adult-onset, incompletely penetrant cancer predisposition gene.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: no functional assay for p.Glu63Lys was reported anywhere, and in-silico benign scores such as REVEL 0.018 do not constitute BS3 functional evidence.	oncokb PMID:26467025 PMID:25394175 generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no family non-segregation data exist for POLD1 c.187G>A; ClinVar Likely benign submissions are classifications, not segregation evidence.	clinvar final_classification_framework generic_acmg_combination_rules
BP1	Not met	Not met: POLD1 disease is caused by exonuclease-domain missense (proofreading loss), not primarily truncating variants (gnomAD pLI ~0, o/e LoF 0.61).	oncokb pvs1_gene_context
BP2	Not met	Not met: no co-occurring pathogenic POLD1 allele is reported — ClinVar's 5 germline submissions and the 2 full-text papers contain no cis/trans phase data.	clinvar oncokb pvs1_gene_context generic_acmg_combination_rules PMID:26467025 PMID:25394175
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.187G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Glu63Lys). 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 moderate strength: REVEL 0.018 is below the <=0.183 moderate BP4 threshold though not below the <=0.016 strong cut-off.	revel
BP5	Not assessed	Not assessed: no proband-level case with an established alternate molecular basis for the disease is available to evaluate BP5.
BP6	Not met	Not met: the ClinVar record (VCV000407981) has zero expert-panel submissions, and its Likely benign label is only an aggregate of three single-submitter laboratories.	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.187G>A in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Glu63Lys). 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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