NM_002691.4:c.3046C>T (p.Arg1016Cys) is a rare missense variant in the polymerase domain of POLD1, present at an extremely low frequency in gnomAD v4.1 (AF=0.00058%, 9/1,541,950 alleles; grpmax FAF=1.78e-05) and absent from gnomAD v2.1 (0/139,430 alleles), supporting PM2 at the supporting level.1 Multiple in silico tools predict a benign effect: REVEL score 0.321 (below 0.5 threshold), BayesDel score -0.248952 (predicting benign), and SpliceAI max delta 0.00, collectively supporting BP4 at the supporting level.2 This variant has been reported in ClinVar as Uncertain significance by three clinical laboratories (ClinVar Variation ID: 408104), and has been observed in COSMIC in one somatic cancer sample. No variant-specific functional studies, segregation data, or case-control data are available.3 With PM2 (supporting) and BP4 (supporting) as the only applicable criteria, the evidence is conflicting and insufficient to classify this variant beyond Uncertain significance.4
POLD1
Final classification
VUS
POLD1 c.3046C>T · p.Arg1016Cys
POLD1
NM_002691.4:c.3046C>T (p.Arg1016Cys) is a rare missense variant in the polymerase domain of POLD1, present at an extremely low frequency in gnomAD v4.1 (AF=0.00058%, 9/1,541,950 alleles; grpmax FAF=1.78e-05) and absent from gnomAD v2.1 (0/139,430 alleles), supporting PM2 at the supporting level.
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.3046C>T
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
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 · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (0/139,430 alleles) and is observed at an extremely low allele frequency in gnomAD v4.1 (AF=0.00058%, 9/1,541,950 alleles, grpmax FAF=1.78e-05), well below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada.
gnomAD v2.1: 0/139430 alleles (AF=0.00%)gnomAD v4.1: 9/1
✓
BP4
supporting
Benign
Multiple in silico tools predict a benign effect: REVEL score 0.321 (below 0.5 threshold), BayesDel score -0.248952 (predicts benign), and SpliceAI delta 0.00 (no splicing impact). These scores collectively support a benign computational prediction.
REVEL: 0.321 (benign range<0.5)BayesDel: -0.248952 (predicts benign)
Assessed · not applied
Pathogenic
PS1
No evidence that the same amino acid change (p.Arg1016Cys) has been established as pathogenic via a different nucleotide change.
PS2
No de novo observation has been reported for NM_002691.4:c.3046C>T in any reviewed source.
PS3
No variant-specific functional studies were identified for NM_002691.4:c.3046C>T (p.Arg1016Cys).
PS4
No case-control or case-series data demonstrate a statistically significant enrichment of NM_002691.4:c.3046C>T in affected individuals compared to controls.
PM1
Residue p.Arg1016 is not located in a statistically significant mutational hotspot.
PM6
No de novo observation has been reported for NM_002691.4:c.3046C>T without confirmation of paternity and maternity.
PP1
No co-segregation data are available for this variant in affected families.
PP2
POLD1 has a non-trivial rate of benign missense variation in the general population.
PP3
Multiple in silico tools predict a benign effect: REVEL score 0.321 (below typical pathogenicity threshold of 0.5), BayesDel score -0.248952 (predicting benign), SpliceAI max delta 0.00 (no splice impact).
PP4
No patient phenotype or family history information is available to assess whether the clinical presentation is specific for POLD1-related disease.
PP5
ClinVar classification is 'Uncertain significance' (3 clinical laboratories, criteria provided, single submitter).
Benign
BA1
The maximum allele frequency in gnomAD v4.1 is 0.00058% (grpmax FAF=0.0018%), far below the 1% BA1 threshold.
BS1
The allele frequency in gnomAD v4.1 is 0.00058%, below the 0.3% BS1 threshold for a rare disease variant.
BS2
No data are available on observation of this variant in healthy adults to assess whether it is observed at high frequency in the context of a fully penetrant dominant disorder.
BS3
No variant-specific functional studies demonstrating no damaging effect on protein function have been published for p.Arg1016Cys.
BS4
No segregation data are available to demonstrate lack of segregation with disease in affected families.
BP2
No data are available on observation of this variant in trans with a known pathogenic POLD1 variant.
BP5
No evidence is available that an alternate molecular basis for disease has been identified in cases carrying NM_002691.4:c.3046C>T.
BP6
ClinVar classification for this variant is 'Uncertain significance,' not benign or likely benign.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.83677e-06; MAF= 0.00058%, 9/1541950 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.47465e-05; MAF= 0.00547%, 4/73064 alleles, homozygotes = 0); grpmax FAF= 1.778e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/139430 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/7116 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00058%
· 9 / 1,541,950
0 hom · FAF 0.0018%
0 hom · FAF 0.0018%
African/African American 4 / 73,064 |
0.0055% |
Remaining individuals 1 / 59,968 |
0.0017% |
European (non-Finnish) 4 / 1,148,446 |
0.00035% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
Absent
· 0 / 139,430
0 hom
0 hom
Not observed in any ancestry group.
+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-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 (3 clinical laboratories). (ClinVarID = 408104)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.321. BayesDel score = -0.248952.
Functional
Likely Oncogenic
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 previously been reported in somatic cancers (COSMIC; COSV113529574, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment
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