NM_001308632.1:c.845C>T (p.Thr282Met) is a missense variant in exon 7 of POLD1. This variant is extremely rare in population databases, with an allele frequency of approximately 0.001% in gnomAD (2/185,056 alleles in v2.1; 16/1,572,202 alleles in v4.1), meeting PM2 at supporting strength.1 Multiple in silico tools predict a benign effect: REVEL score 0.163, BayesDel score -0.403, and SpliceAI max delta score 0.07, meeting BP4 at supporting strength.2 This variant is reported in ClinVar (VCV000537064) as Uncertain significance by two clinical laboratories and Likely benign by one laboratory, with review status 'criteria provided, single submitter.' No expert panel classification is available.3 The variant has been observed in COSMIC (COSV70954170) in 4 somatic cancer samples, but no germline functional data or case-control studies were identified. Two publications in the case record were reviewed for variant-specific evidence. PMID:35534704 (de Oliveira et al., 2022) reported POLD1 as a gene harboring pathogenic/likely pathogenic variants in a Brazilian hereditary cancer cohort but did not mention c.845C>T specifically. PMID:25394175 (Hampel et al., 2015) is an ACMG/NSGC practice guideline for cancer predisposition referral and contains no variant-specific data.4 Overall, the evidence yields one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). The variant remains of uncertain significance.
POLD1
Final classification
VUS
POLD1 c.845C>T · p.Thr282Met
POLD1
NM_001308632.1:c.845C>T (p.Thr282Met) is a missense variant in exon 7 of POLD1. This variant is extremely rare in population databases, with an allele frequency of approximately 0.001% in gnomAD (2/185,056 alleles in v2.1; 16/1,572,202 alleles in v4.1), meeting PM2 at supporting strength.
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 benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
POLD1 c.845C>T
PM2 + BP4
→
VUS
Gene diagram
· NM_001308632.1 · variants mapped to exon structure
POLD1
NM_001308632.1
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 extremely rare in population databases. gnomAD v2.1 reports 2 alleles in 185,056 (AF=0.00108%) and gnomAD v4.1 reports 16 alleles in 1,572,202 (AF=0.00102%), both well below the 0.1% threshold for PM2. No homozygotes have been observed.
gnomAD v2.1: AF=0.00108% (2/185056 alleles0 homozygotes)
✓
BP4
supporting
Benign
Multiple lines of computational evidence support a benign impact. REVEL score is 0.163 (below the typical 0.5 threshold for pathogenicity). BayesDel score is -0.403 (negative, consistent with benign). SpliceAI max delta is 0.07 (no predicted splicing impact). Together these in silico predictions suggest the variant does not disrupt protein function or splicing.
REVEL=0.163 (benign)BayesDel=-0.403 (benign)SpliceAI max delta=0.07 (no splice impact)
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at the same codon producing the same missense change (Thr282Met) was identified in any data source.
PS2
No de novo observation was reported for this variant in any data source.
PS3
No variant-specific functional data was identified.
PS4
No case-control data or statistically significant enrichment of this variant in affected individuals was identified.
PM1
The variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org.
PM5
No same-residue comparator missense variants with established pathogenicity were identified.
PM6
No de novo observation was reported for this variant.
PP1
No cosegregation data is available for this variant.
PP2
While POLD1 is a cancer predisposition gene with known pathogenic missense variants, no gene-level missense constraint data (such as missense Z-score or gnomAD constraint metrics) was available in this case to establish a low rate of benign missense variation required for PP2.
PP3
Multiple in silico tools support a benign impact.
PP4
No specific patient phenotype data is available for this variant.
PP5
ClinVar reports this variant as Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory) with review status 'criteria provided, single submitter.' No expert panel review exists.
Benign
BA1
The overall gnomAD allele frequency is approximately 0.001%, far below the 1% threshold required for BA1.
BS1
The overall gnomAD allele frequency is approximately 0.001%, well below the 0.3% threshold required for BS1.
BS2
No homozygous observations exist in gnomAD (0 homozygotes across all datasets).
BS3
No experimental functional studies were identified that demonstrate no deleterious effect of this variant.
BS4
No segregation data exists for this variant.
BP1
BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease.
BP2
No observation in trans with a known pathogenic variant was reported.
BP5
No observation of this variant in a case with an alternative molecular basis for disease was identified.
BP6
ClinVar reports this variant as Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory) with review status 'criteria provided, single submitter.' The Likely benign classification from Ambry Genetics is a single submitter without expert panel review.
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= 1.01768e-05; MAF= 0.00102%, 16/1572202 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.92983e-05; MAF= 0.00493%, 3/60854 alleles, homozygotes = 0); grpmax FAF= 5.1e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.08075e-05; MAF= 0.00108%, 2/185056 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000204583; MAF= 0.02046%, 1/4888 alleles, homozygotes = 0).
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.001%
· 16 / 1,572,202
0 hom · FAF 0.00051%
0 hom · FAF 0.00051%
Remaining individuals 3 / 60,854 |
0.0049% |
Admixed American 1 / 53,058 |
0.0019% |
African/African American 1 / 74,236 |
0.0013% |
European (non-Finnish) 11 / 1,158,318 |
0.00095% |
+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0011%
· 2 / 185,056
0 hom
0 hom
Remaining individuals 1 / 4,888 |
0.02% |
European (non-Finnish) 1 / 77,708 |
0.0013% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), 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 (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 537064)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.163. BayesDel score = -0.403486.
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 previously been reported in somatic cancers (COSMIC; COSV70954170, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 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
35534704 ↗
The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients.
CLINVAR