About POLD1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLD1 c.2518G>A, p.(Val840Met)
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 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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
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; 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
8 / 1,607,480 alleles
gnomAD v4.1: 8 / 1,607,480 alleles. Recorded AF 4.97673e-06. Recorded homozygote count 0.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
4 reported laboratory submissions
4 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
29 criteria with recorded statuses: 2 met · 17 not met · 4 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=1.6456e-05 (4/243
- 070 alleles)
- 0 homozygotes
- grpmax FAF=7.27e-06.
- gnomAD v4.1: AF=4.9767e-06 (8/1
- 607
- 480 alleles)
- grpmax FAF=2.47e-06.
- gnomAD-Canada v1.0: absent.
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.446 — below damaging threshold of 0.5.
- BayesDel: -0.234 — strongly suggestive of benign.
- SpliceAI: max delta 0.00 — no splicing impact.
Sources
Not met · 17 · evaluated, threshold not reached
PS1 No different nucleotide change at the same amino acid position (Val840) has been established as pathogenic. No comparator variants identified. Details ▾Hide ▴
Evidence considered
- No pathogenic or likely pathogenic variant at codon 840 of POLD1 identified in ClinVar or literature.
Still missing
- No same-residue pathogenic comparators available.
PS2 No de novo occurrence data are available for this variant. No reports of confirmed de novo inheritance were identified. Details ▾Hide ▴
Still missing
- No de novo data available.
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect of p.Val840Met on POLD1 polymerase activity were identified. OncoKB reports no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect. No variant-specific functional assays identified.
Still missing
- No functional studies of p.Val840Met available.
Sources
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. Details ▾Hide ▴
Evidence considered
- Variant prevalence in gnomAD is too low for case-control comparison.
- No published case-control or cohort enrichment data identified.
Still missing
- No case-control data available.
Sources
PM1 Residue Val840 does not lie within a statistically significant mutational hotspot in POLD1 as assessed by hotspot analysis. It is located in the polymerase domain, not in the exonuclease proofreading domain where pathogenic missense variants are most commonly reported. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue_significant=false
- exact_variant_listed='no'.
- Position 840 is in the polymerase catalytic domain
- not the exonuclease proofreading domain.
PM6 No de novo occurrence data with confirmed maternity and paternity are available for this variant. Details ▾Hide ▴
Still missing
- No de novo data with parental confirmation available.
PP2 Insufficient evidence to apply PP2. POLD1 disease mechanism is primarily loss-of-function rather than a well-established pattern of pathogenic missense variation with low benign missense rate. The Z-score and missense constraint data for POLD1 do not independently support PP2 application. Details ▾Hide ▴
Evidence considered
- POLD1 germline disease is primarily associated with LOF (PPAP
- CMMRD-like phenotypes).
- PP2 requires both a low rate of benign missense variation and evidence that missense variants are a common mechanism of disease.
Still missing
- No gene-specific missense constraint metrics readily available to confirm PP2 eligibility.
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.446 (below the standard 0.5 damaging threshold and within indeterminate range). BayesDel score is -0.234 (well below the 0.069 damaging threshold, suggesting benign). SpliceAI max delta score is 0.00 (no predicted splicing impact). In silico consensus does not support pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.446 — borderline/indeterminate (standard damaging threshold >0.5).
- BayesDel: -0.234 — strongly suggestive of benign (damaging threshold >0.069).
- SpliceAI: max delta 0.00 — no splicing impact predicted.
Sources
PP5 This variant is classified as Uncertain Significance in ClinVar by four clinical laboratories. No reputable source (expert panel, clinical guideline) has classified it as pathogenic or likely pathogenic. The ClinVar submissions citing PMID:28492532 and PMID:26467025 reference methodology papers, not variant-specific case evidence. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 469270: Uncertain significance
- review status 'criteria provided
- single submitter'.
- Four clinical laboratories classify as VUS.
- No expert panel or professional society classification as pathogenic.
Still missing
- No reputable source has classified this variant as pathogenic.
Sources
BA1 This variant is extremely rare in population databases. gnomAD v2.1 AF=0.00165% and v4.1 AF=0.00050%, both far below the 1% BA1 threshold for a benign stand-alone classification. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF = 0.00165% (4/243
- 070) << 1% BA1 threshold.
- gnomAD v4.1 overall AF = 0.00050% (8/1
- 607
- 480) << 1% BA1 threshold.
Sources
BS1 This variant is present at extremely low frequency. gnomAD v2.1 AF=0.00165% and v4.1 AF=0.00050%, both well below the 0.3% BS1 threshold for a benign strong classification. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 overall AF = 0.00165% << 0.3% BS1 threshold.
- gnomAD v4.1 overall AF = 0.00050% << 0.3% BS1 threshold.
Sources
BS2 No data are available regarding observation of this variant in healthy adult controls for a fully penetrant POLD1-related disorder. The extremely low population frequency precludes meaningful assessment of BS2. Details ▾Hide ▴
Still missing
- No control cohort data available for POLD1-related fully penetrant disorders.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect of p.Val840Met on protein function have been identified. Absence of functional evidence does not equal evidence of no functional impact. Details ▾Hide ▴
Evidence considered
- No functional studies of p.Val840Met demonstrating normal function identified.
Still missing
- No functional studies available.
BS4 No segregation data demonstrating lack of cosegregation with disease in affected family members are available. Details ▾Hide ▴
Still missing
- No segregation data 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. While POLD1 germline disease is associated with LOF, well-characterized pathogenic missense variants in the exonuclease proofreading domain also exist, so the 'primarily truncating' criterion is not cleanly satisfied for all domains. Residue 840 is in the polymerase domain, but without explicit domain-level BP1 guidance this criterion cannot be confidently applied. Details ▾Hide ▴
Evidence considered
- POLD1 disease mechanism includes both LOF and exonuclease-domain missense variants (PPAP).
- Position 840 is in the polymerase domain
- not the exonuclease domain.
Still missing
- No domain-specific BP1 guidance available for POLD1.
BP2 No evidence of this variant observed in trans with a known pathogenic POLD1 variant. No data are available to assess BP2. Details ▾Hide ▴
Still missing
- No phase data available.
BP6 BP6 requires a reputable source to classify the variant as benign or likely benign. This variant is classified as Uncertain Significance in ClinVar (variation ID 469270) by four clinical laboratories. No source classifies it as benign or likely benign. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- four clinical laboratories.
- No reputable source classifies as benign or likely benign.
Sources
Not assessed · 4 · no assessment recorded
PP1 No segregation data are available for this variant. No family studies with cosegregation analysis were identified. Details ▾Hide ▴
Still missing
- No segregation data available.
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. Details ▾Hide ▴
Still missing
- No proband phenotype data available.
BP5 BP5 typically applies when a variant is found in a case with an alternative molecular basis for disease. No such data are available for this case. Details ▾Hide ▴
Still missing
- No alternative molecular diagnosis data available.
PS5 No family-based allele transmission evidence or statistical linkage data are available for this variant. Details ▾Hide ▴
Still missing
- No segregation or transmission data available.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant (p.Val840Met) does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense variants under the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution (G>A at c.2518
- p.Val840Met) in exon 20/27 of POLD1.
- pvs1_variant_assessment confirms variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ARecessive disorder criterion. POLD1-associated disease is not a confirmed autosomal recessive condition; PM3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AProtein length change criterion specific to non-repeat in-frame deletions/insertions and stop-loss variants. This is a missense substitution; PM4 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable to confirm classic same-residue PM5 semantics; pm5_candidates.json reports no comparator variants at codon 840 with established pathogenicity. Details ▾Hide ▴
Evidence considered
- pm5_candidates: found=false
- eligible_for_classic_pm5_search=false
- 0 same-residue candidates.
Sources
pm5_candidates
BP3 N/AIn-frame indel specific criterion. This variant is a substitution; BP3 is not applicable. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. This variant (c.2518G>A) is a missense substitution (p.Val840Met), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Val840Met)
- not synonymous.
Identifiers
- Gene
- POLD1
- Transcript
- NM_002691.4
- Coding (HGVS c.)
- NM_002691.4:c.2518G>A
- Protein (HGVS p.)
- NP_002682.2:p.(Val840Met)
- GRCh38
- chr19:50414944 G>A
- GRCh37
- chr19:50918201 G>A
- ClinVar
- 469270
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 / 1,607,480 alleles
AF 4.98e-06 · 0 homozygotes · FAF 2.47e-06
gnomAD v2.1
4 / 243,070 alleles
AF 1.65e-05 · 0 homozygotes · FAF 7.27e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5e-06 · 8 / 1,607,480 alleles · 0 hom · FAF 2.5e-06
| African/African American1 / 74,776 | 1.3e-05 |
| European (non-Finnish)7 / 1,176,370 | 6e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 1.6e-05 · 4 / 243,070 alleles · 0 hom · FAF 7.3e-06
| African/African American1 / 15,778 | 6.3e-05 |
| European (non-Finnish)3 / 109,584 | 2.7e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.446
- BayesDel
- -0.234
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.446 — below damaging threshold of 0.5.
- BayesDel: -0.234 — strongly suggestive of benign.
- SpliceAI: max delta 0.00 — no splicing impact.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.446 (below the standard 0.5 damaging threshold and within indeterminate range). BayesDel score is -0.234 (well below the 0.069 damaging threshold, suggesting benign). SpliceAI max delta score is 0.00 (no predicted splicing impact). In silico consensus does not support pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.446 — borderline/indeterminate (standard damaging threshold >0.5).
- BayesDel: -0.234 — strongly suggestive of benign (damaging threshold >0.069).
- SpliceAI: max delta 0.00 — no splicing impact predicted.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. This variant (c.2518G>A) is a missense substitution (p.Val840Met), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Val840Met)
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.446. BayesDel score = -0.234475.
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 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi I et al. · 2016Describes a standardized rules-based DNA variant scoring system (named 'Sherloc' in subsequent publications) for classifying variants in Mendelian disorders. NM_002691.4:c.2518G>A was not identified in this paper.Does not name this variant
-
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. · 2015ACMG/NSGC practice guideline providing referral indications for cancer predisposition assessment. A broad guideline document listing tumor-type-based criteria for genetic counseling referral. NM_002691.4:c.2518G>A was not identified 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
8 / 1,607,480 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
4 Uncertain significance
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/469270/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-50918201-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-50414944-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-50414944-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002691.4%3Ac.2518…
- OncoKB ↗www.oncokb.org/gene/POLD1/V840M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=POLD1+c.2518G%3EA
- 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= 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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
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.