About POLD1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLD1 c.845C>T, p.(Thr282Met)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
16 / 1,572,202 alleles
gnomAD v4.1: 16 / 1,572,202 alleles. Recorded AF 1.01768e-05. Recorded homozygote count 0.
gnomAD 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).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.070 maximum delta
Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
2 Uncertain significance · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV70954170, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
Overall, the evidence yields one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). The variant remains of uncertain significance.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00108% (2/185
- 056 alleles
- 0 homozygotes)
- gnomAD v4.1: AF=0.00102% (16/1
- 572
- 202 alleles
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.163 (benign)
- BayesDel=-0.403 (benign)
- SpliceAI max delta=0.07 (no splice impact)
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No evidence of a different nucleotide change at the same codon producing the same missense change (Thr282Met) was identified in any data source. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at c.845 resulting in p.Thr282Met found in ClinVar
- COSMIC
- or publications
Still missing
- No curated database or literature report of a different nucleotide variant producing the same amino acid substitution
PS2 No de novo observation was reported for this variant in any data source. The available publications and ClinVar submissions do not include de novo testing or parent-of-origin data. Details ▾Hide ▴
Evidence considered
- No de novo data in ClinVar submissions or reviewed literature
Still missing
- No de novo testing data available
PS3 No variant-specific functional data was identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence. No publication in this case reported experimental functional characterization of p.Thr282Met or a systematically characterized range that includes position 282. Details ▾Hide ▴
Evidence considered
- OncoKB reports no reviewed variant-specific functional evidence
- no publications with functional assays for this variant
Still missing
- No experimental functional studies for p.Thr282Met or systematically characterized range including position 282
Sources
PS4 No case-control data or statistically significant enrichment of this variant in affected individuals was identified. The variant has been observed in ClinVar (3 submissions: 2 VUS, 1 LB) and in COSMIC (4 somatic occurrences), but neither source provides odds-ratio or case-control evidence required for PS4. Details ▾Hide ▴
Evidence considered
- ClinVar reports VUS/LB classifications
- COSMIC reports 4 somatic occurrences
- no case-control enrichment data
Still missing
- No case-control studies or odds-ratio data for this variant
Sources
PM1 The variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org. While POLD1 position 282 is within the exonuclease domain region, no variant-specific domain-level literature characterizing this residue as a critical functional site was identified in the case materials. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org reports no significant hotspot at this residue
- no domain-level functional characterization in case literature
Still missing
- No residue-specific domain characterization in literature
- no crystal structure or saturation mutagenesis data for position 282
PM5 No same-residue comparator missense variants with established pathogenicity were identified. The automated PM5 candidate search found no eligible ClinVar entries at position 282. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting returned zero eligible same-residue comparators
Still missing
- No pathogenic missense variants at position 282 in ClinVar to serve as PM5 comparators
Sources
pm5_candidates
PM6 No de novo observation was reported for this variant. PM6 requires a confirmed de novo event with maternity and paternity confirmed; no such data exists in this case. Details ▾Hide ▴
Evidence considered
- No de novo data in any source
Still missing
- No de novo testing or parent-of-origin confirmation
PP1 No cosegregation data is available for this variant. No family studies or pedigree analysis were identified in the case materials. Details ▾Hide ▴
Evidence considered
- No segregation or family study data available
Still missing
- No cosegregation or linkage data
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. Details ▾Hide ▴
Evidence considered
- No missense constraint metrics available for POLD1 in case materials
Still missing
- No gnomAD missense Z-score or constraint data for POLD1
PP3 Multiple in silico tools support a benign impact. REVEL score is 0.163 (below the typical pathogenic threshold of 0.5). BayesDel score is -0.403 (negative, indicative of benign). SpliceAI max delta is 0.07 (no predicted splicing impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.163 (benign)
- BayesDel=-0.403 (benign)
- SpliceAI max delta=0.07 (no splice impact)
Sources
PP4 No specific patient phenotype data is available for this variant. The ClinVar submissions do not include detailed clinical phenotypes, and no publications report variant-specific clinical features. Details ▾Hide ▴
Evidence considered
- No variant-specific phenotype data in ClinVar or reviewed literature
Still missing
- No detailed clinical phenotypes reported for carriers of 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. The current classification does not support a reputable source asserting pathogenicity required for PP5. Even under the PP5 global rule (ClinVar 3-star expert panel for supporting), there is no expert panel submission. Details ▾Hide ▴
Evidence considered
- ClinVar VCV000537064: VUS (2 labs)
- LB (1 lab)
- review status: criteria provided
- single submitter
- no expert panel
Sources
BA1 The overall gnomAD allele frequency is approximately 0.001%, far below the 1% threshold required for BA1. Details ▾Hide ▴
BS1 The overall gnomAD allele frequency is approximately 0.001%, well below the 0.3% threshold required for BS1. Details ▾Hide ▴
BS2 No homozygous observations exist in gnomAD (0 homozygotes across all datasets). BS2 requires observation in homozygous state in healthy adults for a fully penetrant dominant disorder. This variant is too rare to satisfy BS2. Details ▾Hide ▴
Evidence considered
- Zero homozygotes in gnomAD v2.1 (0/185
- 056) and v4.1 (0/1
- 572
- 202)
Sources
BS3 No experimental functional studies were identified that demonstrate no deleterious effect of this variant. The available in silico predictions lean benign (REVEL 0.163, BayesDel -0.403), but these are computational, not experimental, evidence and belong under BP4, not BS3. Details ▾Hide ▴
Evidence considered
- No experimental functional studies demonstrating no deleterious effect
Still missing
- No functional assay data for p.Thr282Met
BS4 No segregation data exists for this variant. BS4 requires lack of cosegregation in affected family members, and no family studies were identified in this case. Details ▾Hide ▴
Evidence considered
- No segregation or family study data available
Still missing
- No cosegregation studies
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. POLD1 is associated with polymerase proofreading-associated polyposis (PPAP), and pathogenic missense variants in the exonuclease domain are a well-established disease mechanism alongside truncating variants. Therefore, POLD1 is not a gene where disease is caused primarily by truncating variants alone. Details ▾Hide ▴
Evidence considered
- POLD1 has both pathogenic missense and truncating variants as known disease mechanisms
- not primarily truncating
Sources
pvs1_gene_context
BP2 No observation in trans with a known pathogenic variant was reported. This variant is too rare in population databases to assess phase with other variants. Details ▾Hide ▴
Evidence considered
- No trans-observation data available
Still missing
- No phase data with pathogenic variants
BP5 No observation of this variant in a case with an alternative molecular basis for disease was identified. No cases were reported where a different pathogenic variant explains the phenotype in an individual also carrying c.845C>T. Details ▾Hide ▴
Evidence considered
- No case with alternative molecular basis reported
Still missing
- No data on cases with alternate molecular explanations
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. Even under the BP6 global rule (ClinVar 3-star expert panel for supporting benign), there is no expert panel submission for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar VCV000537064: VUS (2 labs)
- LB (1 lab)
- review status: criteria provided
- single submitter
- no expert panel
Sources
PS5 No different nucleotide change at the same codon producing the same missense change was identified as pathogenic in any data source. No basis for PS5 application exists. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at c.845 producing p.Thr282Met found in ClinVar or literature
Still missing
- No comparator variant at same codon with established pathogenicity
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution (p.Thr282Met) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
BP7 N/ABP7 applies specifically to synonymous (silent) variants. This variant is a missense substitution (c.845C>T, p.Thr282Met) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only
Identifiers
- Gene
- POLD1
- Transcript
- NM_001308632.1
- Coding (HGVS c.)
- NM_001308632.1:c.845C>T
- Protein (HGVS p.)
- NP_001295561.1:p.(Thr282Met)
- GRCh38
- chr19:50402616 C>T
- GRCh37
- chr19:50905873 C>T
- ClinVar
- 537064
- COSMIC
- COSV70954170
Gene diagram
Every interpreted variant in POLD1, mapped onto the exon structure of NM_001308632.1. Select a row to find it on the plot.
POLD1NM_001308632.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in POLD1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
16 / 1,572,202 alleles
AF 1.02e-05 · 0 homozygotes · FAF 5.1e-06
gnomAD v2.1
2 / 185,056 alleles
AF 1.08e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1e-05 · 16 / 1,572,202 alleles · 0 hom · FAF 5.1e-06
| Remaining individuals3 / 60,854 | 4.9e-05 |
| Admixed American1 / 53,058 | 1.9e-05 |
| African/African American1 / 74,236 | 1.3e-05 |
| European (non-Finnish)11 / 1,158,318 | 9.5e-06 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 1.1e-05 · 2 / 185,056 alleles · 0 hom
| Remaining individuals1 / 4,888 | 0.0002 |
| European (non-Finnish)1 / 77,708 | 1.3e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD 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.
gnomAD 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).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.163
- BayesDel
- -0.403
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL=0.163 (benign)
- BayesDel=-0.403 (benign)
- SpliceAI max delta=0.07 (no splice impact)
Sources
PP3 Multiple in silico tools support a benign impact. REVEL score is 0.163 (below the typical pathogenic threshold of 0.5). BayesDel score is -0.403 (negative, indicative of benign). SpliceAI max delta is 0.07 (no predicted splicing impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.163 (benign)
- BayesDel=-0.403 (benign)
- SpliceAI max delta=0.07 (no splice impact)
Sources
BP7 N/ABP7 applies specifically to synonymous (silent) variants. This variant is a missense substitution (c.845C>T, p.Thr282Met) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.163. BayesDel score = -0.403486.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 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.Hampel H et al. · 2015This is an ACMG/NSGC practice guideline providing referral indications for cancer predisposition assessment. It describes hereditary cancer syndromes and referral criteria at the syndrome level. Neither POLD1 nor the specific variant NM_001308632.1:c.845C>T was mentioned in this guideline.Does not name this variant
-
PMID 35534704 ↗The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients.de Oliveira JM et al. · 2022This study reports the frequency of pathogenic/likely pathogenic germline variants in 1,682 Brazilian individuals tested with multigene hereditary cancer panels. POLD1 was listed among 32 genes harboring pathogenic/likely pathogenic variants, but only at gene level; the specific variant NM_001308632.1:c.845C>T (a VUS, not P/LP) was not mentioned or characterized in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
16 / 1,572,202 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.070
Open source ↗
ClinVar
2 Uncertain significance · 1 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/537064/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-50905873-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-50402616-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-50402616-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001308632.1%3Ac.8…
- OncoKB ↗www.oncokb.org/gene/POLD1/T282M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=209465001
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV70954170, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.