Classification rationale

PM2 BP4 VUS

POLD1 c.187G>A

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.¹ 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.² 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 BP6.³ No variant-specific functional studies, de novo observations, segregation data, or case-control studies were identified in the curated literature.⁴ 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).⁵

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗

4 oncokb ↗

5 generic_acmg_combination_rules

Gene diagram · NM_002691.4 · variants mapped to exon structure

POLD1 NM_002691.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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 v2.1: AF=0.00675%13/192696 alleles

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting Benign

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: 0.018 (strongly predicts benign)BayesDel: -0.510638 (predicts benign)SpliceAI: max delta 0.01 (no splicing impact)

spliceai ↗

Assessed · not applied

Pathogenic

PS1 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 No de novo occurrence data available for this variant; no parental confirmation studies identified.

PS3 No variant-specific functional studies identified in the literature or curated databases.

PS4 No case-control studies or statistically significant enrichment of this variant in affected individuals versus controls has been identified.

PM1 Variant lies at residue 63 in the N-terminal region of POLD1, upstream of the exonuclease domain (residues ~304-490) and polymerase domain.

PM5 No known pathogenic missense variant at the same residue (p.Glu63) has been identified.

PM6 No de novo occurrence data available for this variant; no confirmed de novo reports with maternity/paternity confirmation identified.

PP1 No co-segregation data available for this variant in affected families.

PP2 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 In silico predictions uniformly support a benign interpretation.

PP4 No patient phenotype or family history data available for assessment.

PP5 ClinVar classification is Likely benign / Uncertain significance (Variation ID: 407981) with review status 'criteria provided, single submitter' (1-star).

Benign

BA1 gnomAD allele frequency is 0.00675% (v2.1) and 0.00315% (v4.1), far below the 1% BA1 threshold for a common benign variant.

BS1 gnomAD allele frequency is 0.00675% (v2.1) and 0.00315% (v4.1), well below the 0.3% BS1 threshold.

BS2 No homozygotes observed in gnomAD (v2.1: 0 homozygotes; v4.1: 0 homozygotes).

BS3 No well-established functional studies demonstrating no deleterious effect for this variant.

BS4 No non-segregation data available for this variant in affected families.

BP1 POLD1 is associated with disease through both loss-of-function and missense mechanisms.

BP2 No evidence of observation in trans with a known pathogenic variant in POLD1; no data on allelic phase available.

BP5 No evidence of an alternate molecular basis for disease in this case; no information on other genetic findings available.

BP6 ClinVar classification is Likely benign / Uncertain significance (Variation ID: 407981) with review status 'criteria provided, single submitter' (1-star).

N/A · 2 PVS1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.15175e-05; MAF= 0.00315%, 49/1554692 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000429553; MAF= 0.04296%, 22/51216 alleles, homozygotes = 0); grpmax FAF= 0.00029005.

v2.1

This variant is present in gnomAD v2.1 (AF= 6.74638e-05; MAF= 0.00675%, 13/192696 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000426224; MAF= 0.04262%, 11/25808 alleles, homozygotes = 0); grpmax FAF= 0.00021734.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0032% · 49 / 1,554,692
0 hom · FAF 0.029%

Admixed American 22 / 51,216	0.043%
Remaining individuals 3 / 60,264	0.005%
African/African American 2 / 73,492	0.0027%
European (non-Finnish) 22 / 1,148,928	0.0019%

+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0067% · 13 / 192,696
0 hom · FAF 0.022%

Admixed American 11 / 25,808	0.043%
African/African American 1 / 18,044	0.0055%
European (non-Finnish) 1 / 78,892	0.0013%

+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories). (ClinVarID = 407981)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.018. BayesDel score = -0.510638.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLD1, a DNA polymerase, is infrequently altered by mutation in cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR