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

PM2 supporting BP4 supporting benign

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

NM_002691.4:c.187G>A (p.Glu63Lys) in POLD1 is a rare missense variant absent from population databases at significant frequency (gnomAD v2.1 AF=0.00675%, v4.1 AF=0.00315%), meeting PM2 at supporting strength.

Multiple in silico predictors uniformly support a benign interpretation: REVEL score 0.018 (strongly benign), BayesDel score -0.510638 (benign), and SpliceAI max delta 0.01 (no splicing impact), meeting BP4 at supporting benign strength.

The variant has been reported in ClinVar (Variation ID 407981) as Likely benign by 3 clinical laboratories and as Uncertain significance by 2 clinical laboratories, with review status 'criteria provided, single submitter' (1-star), which does not meet the threshold for PP5 or BP6.

No variant-specific functional studies, de novo observations, segregation data, or case-control studies were identified in the curated literature.

With PM2 (supporting) and BP4 (supporting benign) as the only met criteria, the evidence is insufficient to classify this variant as either pathogenic or benign; this variant remains a Variant of Uncertain Significance (VUS).

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	Missense variant (c.187G>A, p.Glu63Lys) does not fall into null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus variants) required for PVS1 application per ClinGen SVI PVS1 framework (PMC6185798).
PS1	Not met	No previously established pathogenic variant with the same amino acid change (p.Glu63Lys) at this position has been identified in ClinVar or the literature.
PS2	Not met	No de novo occurrence data available for this variant; no parental confirmation studies identified.
PS3	Not met	No variant-specific functional studies identified in the literature or curated databases. OncoKB reports unknown oncogenic effect. REVEL and BayesDel scores are in silico predictors and do not constitute functional evidence for PS3.	oncokb
PS4	Not met	No case-control studies or statistically significant enrichment of this variant in affected individuals versus controls has been identified.
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion; no applicable evidence type defined within the generic ACMG framework.
PM1	Not met	Variant lies at residue 63 in the N-terminal region of POLD1, upstream of the exonuclease domain (residues ~304-490) and polymerase domain. No statistically significant hotspot identified at this residue by cancerhotspots.org. No well-characterized functional domain for which missense variants at this position are established as pathogenic.
PM2	Met	This variant is absent from population databases at significant frequency. gnomAD v2.1 reports an allele frequency of 0.00675% (13/192,696 alleles, no homozygotes); gnomAD v4.1 reports 0.00315% (49/1,554,692 alleles, no homozygotes). Both are well below the 0.1% PM2 threshold for a rare variant in the generic ACMG framework.	gnomad_v2 gnomad_v4
PM5	Not met	No known pathogenic missense variant at the same residue (p.Glu63) has been identified. Automated PM5 candidate search returned no eligible comparators in ClinVar.
PM6	Not met	No de novo occurrence data available for this variant; no confirmed de novo reports with maternity/paternity confirmation identified.
PP1	Not met	No co-segregation data available for this variant in affected families.
PP2	Not met	While POLD1 is a disease-associated gene with pathogenic missense variants (particularly in the exonuclease domain), no gene-level missense constraint metric (e.g., missense Z-score or observed/expected ratio) was provided to establish a low rate of benign missense variation required for PP2.
PP3	Not met	In silico predictions uniformly support a benign interpretation. REVEL score is 0.018 (strongly benign; pathogenic threshold >0.5). BayesDel score is -0.510638 (benign; pathogenic threshold >0.0). SpliceAI max delta is 0.01 (no predicted splicing impact). These scores do not support a pathogenic computational prediction.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data available for assessment. No evidence that the patient's clinical presentation is highly specific for a POLD1-associated disorder.
PP5	Not met	ClinVar classification is Likely benign / Uncertain significance (Variation ID: 407981) with review status 'criteria provided, single submitter' (1-star). Expert panel review (3-star) is required for PP5 application. Current review status does not meet the threshold for reputable-source pathogenic attribution.	clinvar
BA1	Not met	gnomAD allele frequency is 0.00675% (v2.1) and 0.00315% (v4.1), far below the 1% BA1 threshold for a common benign variant.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency is 0.00675% (v2.1) and 0.00315% (v4.1), well below the 0.3% BS1 threshold. The grpmax filtering allele frequency (FAF) is 0.0002173 (v2.1) and 0.0002901 (v4.1), also below threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes observed in gnomAD (v2.1: 0 homozygotes; v4.1: 0 homozygotes). No evidence of observation in healthy adults in a homozygous or hemizygous state.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no deleterious effect for this variant. In silico predictors (REVEL, BayesDel) are computational tools, not experimental functional evidence. No in vitro or in vivo functional assays identified.
BS4	Not met	No non-segregation data available for this variant in affected families.
BP1	Not met	POLD1 is associated with disease through both loss-of-function and missense mechanisms. Pathogenic missense variants are established in this gene, most notably in the exonuclease proofreading domain causing polymerase proofreading-associated polyposis (PPAP). Therefore, a missense variant in POLD1 cannot be presumed benign solely on the basis of variant type.
BP2	Not met	No evidence of observation in trans with a known pathogenic variant in POLD1; no data on allelic phase available.
BP4	Met	Multiple in silico predictors uniformly support a benign interpretation. REVEL score is 0.018 (strongly benign; threshold for pathogenic >0.5). BayesDel score is -0.510638 (benign; threshold for pathogenic >0.0). SpliceAI max delta score is 0.01, predicting no significant splicing impact. Multiple lines of computational evidence agree on absence of deleterious effect.	revel bayesdel spliceai
BP5	Not met	No evidence of an alternate molecular basis for disease in this case; no information on other genetic findings available.
BP6	Not met	ClinVar classification is Likely benign / Uncertain significance (Variation ID: 407981) with review status 'criteria provided, single submitter' (1-star). Expert panel review (3-star) is required for BP6 application. Current review status does not meet the threshold for reputable-source benign attribution.	clinvar
BP7	N/A	Missense variant (c.187G>A, p.Glu63Lys); BP7 applies only to synonymous (silent) variants with no predicted impact on splicing.

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