About POLD1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLD1 c.2953C>T, p.(Arg985Trp)
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: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is present at very low frequency in population databases and remains below the non-VCEP PM2 threshold of 0.1% in both datasets reviewed: gnomAD v2.1 AF 1.07182e-05 (0.00107%, 2/186598) and gnomAD v4.1 AF 5.15439e-06 (0.00052%, 8/1552074). This supports PM2.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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 moderate; combination = 1 moderate, 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
8 / 1,552,074 alleles
gnomAD v4.1: 8 / 1,552,074 alleles. Recorded AF 5.15439e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.07182e-05; MAF= 0.00107%, 2/186598 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.86441e-05; MAF= 0.00586%, 1/17052 alleles, homozygotes = 0).
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 1 met · 7 not met · 15 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The POLD1 c.2953C>T (p.Arg985Trp) variant has been reported in ClinVar as a variant of uncertain significance by five clinical laboratories.
This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 1.07182e-05 (2/186598) and gnomAD v4.1 AF 5.15439e-06 (8/1552074), both below the 0.1% PM2 threshold.
Computational evidence is conflicting: SpliceAI predicts possible splice impact with a max delta score of 0.59, whereas REVEL is low at 0.126 and BayesDel is -0.414351, so PP3 and BP4 are not applied.
No criteria match.
Met · 1
PM2 ModerateThis variant is present at very low frequency in population databases and remains below the non-VCEP PM2 threshold of 0.1% in both datasets reviewed: gnomAD v2.1 AF 1.07182e-05 (0.00107%, 2/186598) and gnomAD v4.1 AF 5.15439e-06 (0.00052%, 8/1552074). This supports PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF 1.07182e-05
- gnomAD v4.1 AF 5.15439e-06
Sources
Not met · 7 · evaluated, threshold not reached
PM1 This residue was not identified in Cancer Hotspots, and available reviewed evidence does not show that p.Arg985 lies in a statistically significant hotspot for this gene. PM1 is therefore not met. Details ▾Hide ▴
Evidence considered
- No hotspot row found for POLD1 R985
Still missing
- No reviewed source in the available materials established this residue as a critical benign-variation-depleted hotspot.
Sources
PP3 Computational evidence is conflicting rather than consistently damaging. SpliceAI predicts possible splice impact with a max delta score of 0.59, but missense predictors are low or not damaging (REVEL 0.126 and BayesDel -0.414351). Because the in silico results do not consistently support a deleterious effect, PP3 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.59
- REVEL 0.126
- BayesDel -0.414351
Still missing
- No RNA study was identified to resolve the predicted splice effect.
Sources
PP5 ClinVar lists this variant as Uncertain significance with single-submitter review status rather than as a pathogenic or likely pathogenic expert classification, so PP5 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- Review status: criteria provided
- single submitter
Sources
BA1 Population frequency does not meet the benign stand-alone threshold of 1%. The highest frequency reviewed was 0.00586% in gnomAD v2.1 African/African American and 0.00355% in gnomAD v4.1 South Asian, both far below 1%. Details ▾Hide ▴
Evidence considered
- Highest subpopulation AF in gnomAD v2.1: 5.86441e-05
- Highest subpopulation AF in gnomAD v4.1: 3.554e-05
Sources
BS1 Population frequency does not exceed the non-VCEP BS1 threshold of 0.3%. The overall AF is 0.00107% in gnomAD v2.1 and 0.00052% in gnomAD v4.1, both well below 0.3%, so BS1 is not met. Details ▾Hide ▴
BP4 Computational evidence does not consistently support a benign interpretation. Although REVEL is low at 0.126 and BayesDel is -0.414351, SpliceAI predicts possible splice impact with a max delta score of 0.59. Because the in silico evidence is conflicting, BP4 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.59
- REVEL 0.126
- BayesDel -0.414351
Still missing
- No RNA study was identified to clarify whether the predicted splice effect is real.
Sources
BP6 ClinVar does not provide a benign or likely benign reputable-source classification for this variant; the reported classification is Uncertain significance, so BP6 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
Sources
Not assessed · 15 · no assessment recorded
PS1 No reviewed evidence identified another nucleotide change causing the same amino acid substitution with an established pathogenic classification, so PS1 cannot be assessed from the available evidence. Details ▾Hide ▴
Still missing
- Same-amino-acid alternate-nucleotide evidence was not identified.
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 is not assessed. Details ▾Hide ▴
Still missing
- No case-level parental testing data were identified.
PS3 No well-established functional study showing a damaging effect of p.(Arg985Trp) was identified, so PS3 is not assessed. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify reviewed variant-specific functional evidence
Still missing
- No variant-specific functional assay was identified.
Sources
PS4 No case-control enrichment or affected-individual series demonstrating a significant excess of this variant in disease was identified, so PS4 is not assessed. Details ▾Hide ▴
Evidence considered
- ClinVar VUS record only
- Variant present at very low frequency in gnomAD
Still missing
- No affected-case enrichment data were identified for this exact variant.
Sources
PM5 No reviewed evidence identified a different pathogenic missense change at the same amino acid residue, so PM5 is not assessed. Details ▾Hide ▴
Still missing
- No pathogenic alternate missense substitution at codon 985 was identified.
PM6 No apparent de novo report without full parental confirmation was identified for this variant, so PM6 is not assessed. Details ▾Hide ▴
Still missing
- No suggestive de novo case report was identified.
PP1 No segregation data were identified for this variant, so PP1 is not assessed. Details ▾Hide ▴
Still missing
- No pedigree or meiosis data were identified.
PP2 Available reviewed sources do not establish a gene-level missense pattern that would support PP2 for this variant, so PP2 is not assessed. Details ▾Hide ▴
Still missing
- No reviewed gene-level missense constraint framework was identified in the available materials.
PP4 No individual-level phenotype or family history data were provided that would support a highly specific clinical presentation for this variant, so PP4 is not assessed. Details ▾Hide ▴
Still missing
- Phenotype-specific case information was not identified.
BS2 Available reviewed evidence does not document this variant in a sufficient number of unaffected adults for the relevant disorder context, so BS2 is not assessed. Details ▾Hide ▴
Evidence considered
- Rare population observations without phenotype data
Still missing
- No healthy adult observation dataset specific to this criterion was identified.
Sources
BS3 No well-established functional study showing a normal or non-damaging effect of p.(Arg985Trp) was identified, so BS3 is not assessed. Details ▾Hide ▴
Evidence considered
- No reviewed variant-specific functional evidence identified
Still missing
- No variant-specific benign functional assay was identified.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 is not assessed. Details ▾Hide ▴
Still missing
- No family study demonstrating lack of segregation was identified.
BP1 Available reviewed evidence does not establish that missense variants in this gene are generally a poor mechanism of disease, so BP1 is not assessed. Details ▾Hide ▴
Still missing
- No reviewed gene-level mechanism summary supporting BP1 was identified in the available materials.
BP2 No phase or co-occurrence data with another pathogenic variant were identified for this variant, so BP2 is not assessed. Details ▾Hide ▴
Still missing
- No cis/trans or co-occurrence information was identified.
BP5 No alternate molecular explanation or independent cause for the phenotype was identified from the available evidence, so BP5 is not assessed. Details ▾Hide ▴
Still missing
- Clinical correlation and alternate diagnosis data were not identified.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Arg985Trp), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site variants. Although gene-level review supports that loss of function can be a disease mechanism in POLD1, the variant-specific PVS1 scaffold does not support applying PVS1 to this change. Details ▾Hide ▴
Evidence considered
- Missense change p.(Arg985Trp)
- Generic PVS1 scaffold marked variant_bucket as other and apply_generic_pvs1_framework as false
Sources
pvs1_gene_contextpvs1_variant_assessment
PM3 N/APM3 is used for recessive disorders with evidence of trans occurrence, and no such recessive context or phase data were identified for this variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis variant is a missense substitution and is not an in-frame deletion, in-frame insertion, or stop-loss variant, so PM4 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis variant is a missense substitution rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- POLD1
- Transcript
- NM_002691.4
- Coding (HGVS c.)
- NM_002691.4:c.2953C>T
- Protein (HGVS p.)
- NP_002682.2:p.(Arg985Trp)
- GRCh38
- chr19:50416528 C>T
- GRCh37
- chr19:50919785 C>T
Gene diagram
Every interpreted variant in POLD1, mapped onto the exon structure of NM_002691.4. Select a row to find it on the plot.
POLD1NM_002691.4
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
8 / 1,552,074 alleles
AF 5.15e-06 · 0 homozygotes · FAF 9.44e-06
gnomAD v2.1
2 / 186,598 alleles
AF 1.07e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 5.2e-06 · 8 / 1,552,074 alleles · 0 hom · FAF 9.4e-06
| South Asian3 / 84,412 | 3.6e-05 |
| African/African American1 / 73,290 | 1.4e-05 |
| European (non-Finnish)4 / 1,149,942 | 3.5e-06 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 1.1e-05 · 2 / 186,598 alleles · 0 hom
| African/African American1 / 17,052 | 5.9e-05 |
| South Asian1 / 23,132 | 4.3e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.15439e-06; MAF= 0.00052%, 8/1552074 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.554e-05; MAF= 0.00355%, 3/84412 alleles, homozygotes = 0); grpmax FAF= 9.44e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.07182e-05; MAF= 0.00107%, 2/186598 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.86441e-05; MAF= 0.00586%, 1/17052 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Computational evidence is conflicting rather than consistently damaging. SpliceAI predicts possible splice impact with a max delta score of 0.59, but missense predictors are low or not damaging (REVEL 0.126 and BayesDel -0.414351). Because the in silico results do not consistently support a deleterious effect, PP3 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.59
- REVEL 0.126
- BayesDel -0.414351
Still missing
- No RNA study was identified to resolve the predicted splice effect.
Sources
BP4 Computational evidence does not consistently support a benign interpretation. Although REVEL is low at 0.126 and BayesDel is -0.414351, SpliceAI predicts possible splice impact with a max delta score of 0.59. Because the in silico evidence is conflicting, BP4 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.59
- REVEL 0.126
- BayesDel -0.414351
Still missing
- No RNA study was identified to clarify whether the predicted splice effect is real.
Sources
BP7 N/AThis variant is a missense substitution rather than a synonymous or deep intronic change, so BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.59). REVEL score = 0.126. BayesDel score = -0.414351.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
8 / 1,552,074 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/537107/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-50919785-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-50416528-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002691.4%3Ac.2953…
- OncoKB ↗www.oncokb.org/gene/POLD1/R985W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLD1+c.2953C%3ET
- 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= 5.15439e-06; MAF= 0.00052%, 8/1552074 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.554e-05; MAF= 0.00355%, 3/84412 alleles, homozygotes = 0); grpmax FAF= 9.44e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.07182e-05; MAF= 0.00107%, 2/186598 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.86441e-05; MAF= 0.00586%, 1/17052 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.59). REVEL score = 0.126. BayesDel score = -0.414351.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.