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.1 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.2 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.3 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.4
POLD1
Final classification
VUS
POLD1 c.2518G>A · p.Val840Met
POLD1
The variant NM_002691.4:c.2518G>A (p.Val840Met) is a missense substitution in exon 20 of POLD1.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
POLD1 c.2518G>A
PM2 + BP4
→
VUS
Gene diagram
· NM_002691.4 · variants mapped to exon structure
POLD1
NM_002691.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: AF=1.6456e-05 (4/243070 alleles)0 homozygotes
✓
BP4
supporting
Benign
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: 0.446 — below damaging threshold of 0.5.BayesDel: -0.234 — strongly suggestive of benign.SpliceAI: max delta 0.00 — no splicing impact.
Assessed · not applied
Pathogenic
PS1
No different nucleotide change at the same amino acid position (Val840) has been established as pathogenic.
PS2
No de novo occurrence data are available for this variant.
PS3
No well-established in vitro or in vivo functional studies demonstrating a damaging effect of p.Val840Met on POLD1 polymerase activity were identified.
PS4
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.
PM1
Residue Val840 does not lie within a statistically significant mutational hotspot in POLD1 as assessed by hotspot analysis.
PM6
No de novo occurrence data with confirmed maternity and paternity are available for this variant.
PP1
No segregation data are available for this variant.
PP2
Insufficient evidence to apply PP2.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
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
This variant is classified as Uncertain Significance in ClinVar by four clinical laboratories.
Benign
BA1
This variant is extremely rare in population databases.
BS1
This variant is present at extremely low frequency.
BS2
No data are available regarding observation of this variant in healthy adult controls for a fully penetrant POLD1-related disorder.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect of p.Val840Met on protein function have been identified.
BS4
No segregation data demonstrating lack of cosegregation with disease in affected family members are available.
BP1
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.
BP2
No evidence of this variant observed in trans with a known pathogenic POLD1 variant.
BP5
BP5 typically applies when a variant is found in a case with an alternative molecular basis for disease.
BP6
BP6 requires a reputable source to classify the variant as benign or likely benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.97673e-06; MAF= 0.00050%, 8/1607480 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33733e-05; MAF= 0.00134%, 1/74776 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.64562e-05; MAF= 0.00165%, 4/243070 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.33794e-05; MAF= 0.00634%, 1/15778 alleles, homozygotes = 0); grpmax FAF= 7.27e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0005%
· 8 / 1,607,480
0 hom · FAF 0.00025%
0 hom · FAF 0.00025%
African/African American 1 / 74,776 |
0.0013% |
European (non-Finnish) 7 / 1,176,370 |
0.0006% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0016%
· 4 / 243,070
0 hom · FAF 0.00073%
0 hom · FAF 0.00073%
African/African American 1 / 15,778 |
0.0063% |
European (non-Finnish) 3 / 109,584 |
0.0027% |
+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 469270)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.446. BayesDel score = -0.234475.
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.
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.
Sources & reference links
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