LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-13
Case ID: NM_002691.4_c.49C_T_20261013_203439
Framework: ACMG/AMP 2015
Variant classification summary

NM_002691.4:c.49C>T

POLD1  · NP_002682.2:p.(Arg17Trp)  · NM_002691.4
GRCh37: chr19:50902157 C>T  ·  GRCh38: chr19:50398900 C>T
Gene: POLD1 Transcript: NM_002691.4
Final call
VUS
PM2 supporting PP2 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.(Arg17Trp)
gnomAD AF
1.559688661188208e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (supporting): variant is rare in gnomAD (v4.1 grpmax FAF 5.28e-05, below 0.0001) and absent from gnomAD-Canada.
2
PP2 (supporting): POLD1 is a disease gene in which missense change is an established pathogenic mechanism, including germline exonuclease-domain alleles.
3
BP4 (supporting): REVEL 0.095 is below the 0.250 in-silico threshold, indicating the missense substitution is computationally tolerated.
4
VUS: two supporting pathogenic criteria and one supporting benign criterion satisfy no ACMG pathogenic, likely pathogenic, benign or likely benign combination.
Final determination: Under generic ACMG/AMP 2015, two supporting pathogenic criteria (PM2, PP2) and one supporting benign criterion (BP4) reach no pathogenic, likely pathogenic, benign or likely benign combination threshold, 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.49C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Arg17Trp). 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.Arg17Trp record (ClinVar 408109) is conflicting VUS/likely benign at 1 star, so no established pathogenic same-amino-acid comparator exists.
clinvar pm5_candidates generic_acmg_combination_rules
PS2 Not assessed Not assessed: no proband, parental testing or parentage confirmation exists for c.49C>T, so de novo status cannot be established.
generic_acmg_combination_rules final_classification_framework clinvar PMID:25741868 PMID:25394175 PMID:30093976
PS3 Not assessed Not assessed: no functional assay of POLD1 p.Arg17Trp was reported, so the generic ACMG PS3 requirement for a well-established damaging-effect study is unmet.
oncokb clinvar PMID:25741868 PMID:26467025
PS4 Not met Not met: no odds ratio or relative risk exists for this variant to compare against the generic PS4 threshold of OR/RR > 5.0.
clinvar gnomad_v2 gnomad_v4 PMID:25741868 PMID:25394175 PMID:30093976 PMID:26467025
PM1 Not met Not met: residue 17 of 1107 lies outside POLD1's exonuclease proofreading domain where pathogenic missense variants cluster, and POLD1 R17 is not a reported hotspot.
oncokb pvs1_gene_context generic_acmg_combination_rules
PM2 Met Met at supporting: gnomAD v4.1 grpmax FAF 5.28e-05 is below the <=0.0001 PM2 threshold, with variant absent from gnomAD-Canada.
gnomad_v2 gnomad_v4 PMID:25741868
PM3 Not assessed Not assessed: no proband genotype, second POLD1 allele, or phase data exists, with zero homozygotes in gnomAD v4.1 (25/1,602,884 alleles).
clinvar final_classification_framework gnomad_canada gnomad_v2 gnomad_v4 oncokb PMID:25741868 pvs1_gene_context
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.49C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Arg17Trp). 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: no pathogenic missense at Arg17 exists; ClinVar's only codon-17 POLD1 record is the variant under assessment (408109, VUS/likely benign) and the same-residue harvest found zero comparators.
pm5_candidates clinvar generic_acmg_combination_rules
PM6 Not assessed Not assessed: no proband or parent-of-origin information exists, so no assumed de novo occurrence can be documented for c.49C>T.
generic_acmg_combination_rules final_classification_framework clinvar PMID:25741868 PMID:25394175 PMID:30093976
PP1 Not assessed Not assessed: no pedigree, affected relatives or meioses are available, so co-segregation of c.49C>T with disease cannot be evaluated.
generic_acmg_combination_rules final_classification_framework clinvar PMID:25741868 PMID:26467025 PMID:30093976
PP2 Met Met at supporting: POLD1 is a Mendelian disease gene in which exonuclease-domain missense variants such as p.Asp402Asn are a common pathogenic mechanism, satisfying PP2's missense-mechanism requirement.
oncokb pvs1_gene_context gnomad_v2 clinvar generic_acmg_combination_rules
PP3 Not met Not met: REVEL 0.095 is below the >=0.644 PP3 supporting threshold for this missense variant.
revel
PP4 Not met Not met: no proband phenotype or family history is documented, and the only reported phenotype (breast cancer) is not specific for POLD1-associated disease.
clinvar PMID:25741868 final_classification_framework
PP5 Not met Not met: VCV000408109 has 0 expert-panel submissions (1-star, conflicting ordinary laboratory assertions), so no exact-variant expert-panel classification exists.
clinvar PMID:25741868 final_classification_framework
BA1 Not met Not met: gnomAD total allele frequency 1.6e-05 (25/1.6M, v4.1) is far below the >=0.05 BA1 stand-alone threshold.
gnomad_v2 gnomad_v4 PMID:25741868
BS1 Not met Not met: gnomAD v4.1 total AF 1.6e-05 and grpmax FAF 5.3e-05 both fall far below the >=0.01 BS1 threshold.
gnomad_v2 gnomad_v4 PMID:25741868
BS2 Not met Not met: zero homozygotes in gnomAD and POLD1 PPAP is adult-onset with incomplete penetrance, failing BS2's early-onset full-penetrance premise.
gnomad_v2 gnomad_v4 PMID:25741868
BS3 Not assessed Not assessed: no functional assay of POLD1 p.Arg17Trp was reported, so the generic ACMG BS3 requirement for a well-established no-damaging-effect study is unmet.
oncokb clinvar PMID:25741868 PMID:26467025
BS4 Not assessed Not assessed: no family with genotyped affected and unaffected members exists, so non-segregation of c.49C>T cannot be demonstrated.
generic_acmg_combination_rules final_classification_framework clinvar PMID:25741868 PMID:26467025 PMID:30093976
BP1 Not met Not met: POLD1 disease is not truncating-only, as germline exonuclease-domain missense variants such as p.Asp402Asn and p.Ile494Ser cause polymerase proofreading-associated polyposis.
oncokb pvs1_gene_context generic_acmg_combination_rules
BP2 Not assessed Not assessed: no phased pathogenic POLD1 partner allele exists in any source, with zero homozygotes in gnomAD v4.1 (25/1,602,884 alleles).
clinvar final_classification_framework gnomad_canada gnomad_v2 gnomad_v4 oncokb PMID:25741868 pvs1_gene_context
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.49C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Arg17Trp). 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, supporting: REVEL 0.095 is at or below the <=0.29 BP4 supporting threshold for this missense variant.
revel
BP5 Not met Not met: no case with an alternate molecular basis is documented (no proband, co-occurring pathogenic variant, or second diagnosis in any source).
clinvar PMID:25741868 final_classification_framework
BP6 Not met Not met: VCV000408109 has 0 expert-panel submissions; its single Likely-benign entry is an ordinary single-submitter laboratory assertion that cannot trigger BP6.
clinvar PMID:25741868 final_classification_framework
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.49C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Arg17Trp). 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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