NM_002691.4:c.2518G>A

POLD1 · NP_002682.2:p.(Val840Met) · NM_002691.4

GRCh37: chr19:50918201 G>A · GRCh38: chr19:50414944 G>A

Gene: POLD1 Transcript: NM_002691.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Val840Met)

gnomAD AF

4.976733769626993e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The variant NM_002691.4:c.2518G>A (p.Val840Met) is a missense substitution in exon 20 of POLD1.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency 0.00165% (4/243,070 alleles) and gnomAD v4.1 allele frequency 0.00050% (8/1,607,480 alleles), meeting PM2 at supporting level.

Multiple lines of computational evidence suggest no deleterious impact: REVEL score 0.446 (below the 0.5 damaging threshold), BayesDel score -0.234 (well below the 0.069 damaging cutoff), and SpliceAI max delta 0.00 (no predicted splicing impact), meeting BP4 at supporting level.

This variant is classified as Uncertain Significance in ClinVar (variation ID 469270) by four clinical laboratories. No expert panel or professional society has classified it as pathogenic or benign.

No functional studies, segregation data, case-control analyses, or de novo reports were identified for this variant. Computational evidence is equivocal with a borderline REVEL score.

Applying the generic ACMG/AMP 2015 classification framework, the evidence profile consists of one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), which cancel out. The variant remains a Variant of Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, 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	This missense variant (p.Val840Met) does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense variants under the generic ACMG/AMP framework.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No different nucleotide change at the same amino acid position (Val840) has been established as pathogenic. No comparator variants identified.
PS2	Not met	No de novo occurrence data are available for this variant. No reports of confirmed de novo inheritance were identified.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect of p.Val840Met on POLD1 polymerase activity were identified. OncoKB reports no variant-specific functional evidence.	oncokb
PS4	Not met	The variant is extremely rare (gnomAD v2.1 AF=0.00165%, v4.1 AF=0.00050%) and no case-control studies demonstrating statistically significant enrichment in affected individuals over controls have been performed.	gnomad_v2 gnomad_v4
PS5	Not assessed	No family-based allele transmission evidence or statistical linkage data are available for this variant.
PM1	Not met	Residue Val840 does not lie within a statistically significant mutational hotspot in POLD1 as assessed by hotspot analysis. It is located in the polymerase domain, not in the exonuclease proofreading domain where pathogenic missense variants are most commonly reported.
PM2	Met	This variant is absent from or present at extremely low frequency in large population cohorts. gnomAD v2.1: 4/243,070 alleles (AF=0.00165%); gnomAD v4.1: 8/1,607,480 alleles (AF=0.00050%). Both are well below the 0.1% PM2 threshold. No homozygotes reported.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Unable to confirm classic same-residue PM5 semantics; pm5_candidates.json reports no comparator variants at codon 840 with established pathogenicity.	pm5_candidates
PM6	Not met	No de novo occurrence data with confirmed maternity and paternity are available for this variant.
PP1	Not assessed	No segregation data are available for this variant. No family studies with cosegregation analysis were identified.
PP2	Not met	Insufficient evidence to apply PP2. POLD1 disease mechanism is primarily loss-of-function rather than a well-established pattern of pathogenic missense variation with low benign missense rate. The Z-score and missense constraint data for POLD1 do not independently support PP2 application.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.446 (below the standard 0.5 damaging threshold and within indeterminate range). BayesDel score is -0.234 (well below the 0.069 damaging threshold, suggesting benign). SpliceAI max delta score is 0.00 (no predicted splicing impact). In silico consensus does not support pathogenicity.	revel bayesdel spliceai
PP4	Not assessed	No detailed phenotypic data or clinical syndrome information specific to this proband are available to assess whether the patient's phenotype is highly specific for POLD1-related disease.
PP5	Not met	This variant is classified as Uncertain Significance in ClinVar by four clinical laboratories. No reputable source (expert panel, clinical guideline) has classified it as pathogenic or likely pathogenic. The ClinVar submissions citing PMID:28492532 and PMID:26467025 reference methodology papers, not variant-specific case evidence.	clinvar
BA1	Not met	This variant is extremely rare in population databases. gnomAD v2.1 AF=0.00165% and v4.1 AF=0.00050%, both far below the 1% BA1 threshold for a benign stand-alone classification.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is present at extremely low frequency. gnomAD v2.1 AF=0.00165% and v4.1 AF=0.00050%, both well below the 0.3% BS1 threshold for a benign strong classification.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of this variant in healthy adult controls for a fully penetrant POLD1-related disorder. The extremely low population frequency precludes meaningful assessment of BS2.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect of p.Val840Met on protein function have been identified. Absence of functional evidence does not equal evidence of no functional impact.
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease in affected family members are available.
BP1	Not met	BP1 requires a missense variant in a gene where primarily truncating (null) variants cause disease and there is a low prior expectation of pathogenic missense variants. While POLD1 germline disease is associated with LOF, well-characterized pathogenic missense variants in the exonuclease proofreading domain also exist, so the 'primarily truncating' criterion is not cleanly satisfied for all domains. Residue 840 is in the polymerase domain, but without explicit domain-level BP1 guidance this criterion cannot be confidently applied.
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic POLD1 variant. No data are available to assess BP2.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.446 (below the standard 0.5 damaging threshold). BayesDel score is -0.234 (below the 0.069 damaging cutoff, supportive of benign). SpliceAI max delta is 0.00 (no splicing impact predicted). Taken together, the computational consensus suggests a benign effect.	revel bayesdel spliceai
BP5	Not assessed	BP5 typically applies when a variant is found in a case with an alternative molecular basis for disease. No such data are available for this case.
BP6	Not met	BP6 requires a reputable source to classify the variant as benign or likely benign. This variant is classified as Uncertain Significance in ClinVar (variation ID 469270) by four clinical laboratories. No source classifies it as benign or likely benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splicing impact. This variant (c.2518G>A) is a missense substitution (p.Val840Met), not a synonymous variant.
BP3	N/A	In-frame indel specific criterion. This variant is a substitution; BP3 is not applicable.
PM3	N/A	Recessive disorder criterion. POLD1-associated disease is not a confirmed autosomal recessive condition; PM3 is not applicable.
PM4	N/A	Protein length change criterion specific to non-repeat in-frame deletions/insertions and stop-loss variants. This is a missense substitution; PM4 is not applicable.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.