NM_002691.4:c.353C>T

POLD1 · NP_002682.2:p.(Ser118Phe) · NM_002691.4

GRCh37: chr19:50905071 C>T · GRCh38: chr19:50401814 C>T

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

BP4 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Ser118Phe)

gnomAD AF

7.871487735974187e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

BP4 supporting: REVEL 0.099 is below the benign computational threshold.

VUS: BP4 alone is insufficient for the generic ACMG/AMP Likely Benign or Benign thresholds.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting benign criterion does not meet the two-supporting-criteria threshold for Likely Benign, so the result is VUS.

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.353C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Ser118Phe). 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 assessed	Not assessed: no validated pathogenic POLD1 substitution producing the same p.Ser118Phe amino-acid change was identified.	clinvar
PS2	Not assessed	Not assessed: no documented affected proband with confirmed absence of the variant in both tested biological parents.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay, assay controls, or quantitative biological readout was reported for POLD1 p.Ser118Phe.
PS4	Not assessed	Not assessed: no variant-specific case-control enrichment, odds ratio, likelihood ratio, or affected-versus-control prevalence data are available.
PM1	Not met	Not met: POLD1 S118 is not in a documented hotspot, and no approved critical-domain evidence places residue 118 in a PM1 region.	oncokb
PM2	Not met	Not met: aggregate AF is below 0.0001, but ancestry-specific frequencies reach 0.000696185 in gnomAD v2.1 and exceed the PM2 threshold.	gnomad_v2 gnomad_v4 clinvar generic_acmg_combination_rules PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband biallelic observation or verified pathogenic variant in trans is documented for this POLD1 variant.
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.353C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Ser118Phe). 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 assessed	Not assessed: no validated pathogenic missense comparator at POLD1 residue Ser118 was available for PM5.
PM6	Not assessed	Not assessed: no suspected de novo observation with compatible phenotype and parental testing or parentage information is reported.
PP1	Not assessed	Not assessed: no informative affected-relative or unaffected-relative genotypes and no segregation meioses are documented.
PP2	Not assessed	Not assessed: no gene-specific POLD1 evidence establishes both a dominant missense mechanism and a low benign-missense rate for PP2.	oncokb
PP3	Not met	Not met: REVEL 0.099 is below the PP3 supporting threshold of >=0.644 for missense variants.	revel
PP4	Not assessed	Not assessed: no carrier phenotype or clinical diagnosis is provided to evaluate specificity for a POLD1-related disorder.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant and no qualifying Pathogenic or Likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: the highest default all-comers subpopulation frequency is 0.000696185, far below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25741868
BS1	Not met	Not met: the highest default all-comers subpopulation frequency, 0.000696185, is about 14-fold below the 0.01 BS1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not met	Not met: all available datasets show zero homozygotes, and gnomAD provides no phenotype or age data proving any carrier is a healthy adult.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules PMID:25741868
BS3	Not assessed	Not assessed: no variant-specific validated assay demonstrated preserved POLD1 function with appropriate controls or a quantitative benign-effect result.
BS4	Not assessed	Not assessed: no tested unaffected relatives with documented non-segregation and reliable phenotype information are reported.
BP1	Not assessed	Not assessed: POLD1 is missense here, but predominant truncating-variant disease mechanism has not been established for BP1.
BP2	Not assessed	Not assessed: no documented co-occurrence or phase result shows this variant with another pathogenic or likely pathogenic variant.
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.353C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Ser118Phe). 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: REVEL 0.099 is below the BP4 supporting threshold of <=0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no alternative molecular diagnosis or evidence that another variant explains the patient's phenotype is documented.
BP6	Not met	Not met: ClinVar has zero expert-panel submissions, so its ordinary Likely benign laboratory assertions 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.353C>T in POLD1 is a missense substitution predicted to produce NP_002682.2:p.(Ser118Phe). 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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