About POLD1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLD1 c.3046C>T, p.(Arg1016Cys)
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 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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
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
9 / 1,541,950 alleles
gnomAD v4.1: 9 / 1,541,950 alleles. Recorded AF 5.83677e-06. Recorded homozygote count 0.
gnomAD 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).
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
3 reported laboratory submissions
3 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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV113529574, n = 1 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.
29 criteria with recorded statuses: 2 met · 14 not met · 5 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
With PM2 (supporting) and BP4 (supporting) as the only applicable criteria, the evidence is conflicting and insufficient to classify this variant beyond Uncertain significance.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/139
- 430 alleles (AF=0.00%)
- gnomAD v4.1: 9/1
- 541
- 950 alleles (AF=0.00058%)
- grpmax FAF=1.78e-05
- gnomAD-Canada: absent
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.321 (benign range
- <0.5)
- BayesDel: -0.248952 (predicts benign)
- SpliceAI: max delta 0.00 (no splice alteration predicted)
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No evidence that the same amino acid change (p.Arg1016Cys) has been established as pathogenic via a different nucleotide change. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide change producing p.Arg1016Cys was identified in ClinVar or the reviewed literature.
Still missing
- No ClinVar or literature search for same-amino-acid alternate nucleotide changes was conducted beyond the standard evidence pipeline.
PS2 No de novo observation has been reported for NM_002691.4:c.3046C>T in any reviewed source. Details ▾Hide ▴
Evidence considered
- No de novo data found in ClinVar submissions or literature.
Still missing
- No proband or parental testing data available.
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. PMID:25394175 is an ACMG practice guideline and does not report variant-specific prevalence. Details ▾Hide ▴
Evidence considered
- PMID:25394175 is a practice guideline on cancer predisposition assessment referral
- not a case-observation study.
Still missing
- No case-control studies or cohort frequency comparisons available.
Sources
PM1 Residue p.Arg1016 is not located in a statistically significant mutational hotspot. No evidence was found that this residue lies within a critical functional domain devoid of benign variation. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue not significant
- exact variant not listed as recurrent.
Still missing
- No domain-level constraint analysis available for POLD1 exonuclease/polymerase domains at this residue.
PM6 No de novo observation has been reported for NM_002691.4:c.3046C>T without confirmation of paternity and maternity. Details ▾Hide ▴
Evidence considered
- No de novo data in reviewed sources.
Still missing
- No trio or parent-child testing data available.
PP1 No co-segregation data are available for this variant in affected families. Details ▾Hide ▴
Evidence considered
- No segregation analysis reported in any reviewed source.
Still missing
- No family studies or segregation data available.
PP2 POLD1 has a non-trivial rate of benign missense variation in the general population. No gene-specific constraint data support a low rate of benign missense variation relative to disease-causing missense variants. Details ▾Hide ▴
Evidence considered
- No gene-level missense constraint metric (e.g.
- missense Z-score) available to support PP2.
Still missing
- No POLD1-specific missense constraint analysis.
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). No in silico evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.321 (not deleterious
- threshold typically ≥0.5)
- BayesDel: -0.248952 (predicts benign)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
PP5 ClinVar classification is 'Uncertain significance' (3 clinical laboratories, criteria provided, single submitter). No reputable source has classified NM_002691.4:c.3046C>T as pathogenic or likely pathogenic. PMID:25394175 is a practice guideline that does not report a classification for this variant; PMID:28492532 describes criteria methodology, not variant classification. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS (3 submitters)
- review status 'criteria provided
- single submitter'
- No expert panel or multiple-submitter pathogenic assertion
Sources
BA1 The maximum allele frequency in gnomAD v4.1 is 0.00058% (grpmax FAF=0.0018%), far below the 1% BA1 threshold. Details ▾Hide ▴
BS1 The allele frequency in gnomAD v4.1 is 0.00058%, below the 0.3% BS1 threshold for a rare disease variant. Details ▾Hide ▴
BS4 No segregation data are available to demonstrate lack of segregation with disease in affected families. Details ▾Hide ▴
Evidence considered
- No family studies available.
Still missing
- No segregation or non-segregation data.
BP5 No evidence is available that an alternate molecular basis for disease has been identified in cases carrying NM_002691.4:c.3046C>T. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis reported for carriers of this variant.
Still missing
- No data on co-occurring pathogenic variants in other genes in carriers.
BP6 ClinVar classification for this variant is 'Uncertain significance,' not benign or likely benign. No reputable source has classified this variant as benign. Details ▾Hide ▴
Not assessed · 5 · no assessment recorded
PS3 No variant-specific functional studies were identified for NM_002691.4:c.3046C>T (p.Arg1016Cys). OncoKB notes gene-level context only. Full-text review of PMID:27149842 and PMID:29056344 did not mention this variant. No in vitro or in vivo functional data are available to adjudicate PS3. Details ▾Hide ▴
Evidence considered
- OncoKB classification 'Likely Oncogenic' is gene-level
- not variant-specific.
- Full-text of PMID:27149842 and PMID:29056344 reviewed
- variant not mentioned.
Still missing
- No variant-specific functional assays (e.g.
- polymerase activity
- proofreading capacity) have been published for p.Arg1016Cys.
Sources
PP4 No patient phenotype or family history information is available to assess whether the clinical presentation is specific for POLD1-related disease. Details ▾Hide ▴
Evidence considered
- No phenotype data provided for this case.
Still missing
- Patient phenotype and family history not available.
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. Details ▾Hide ▴
Evidence considered
- No healthy cohort data specific to this variant.
Still missing
- No phenotype data on the 9 gnomAD v4.1 carriers to confirm healthy status.
BS3 No variant-specific functional studies demonstrating no damaging effect on protein function have been published for p.Arg1016Cys. Details ▾Hide ▴
Evidence considered
- No in vitro or in vivo functional data demonstrating benign effect.
Still missing
- No polymerase activity or proofreading functional assays for this variant.
BP2 No data are available on observation of this variant in trans with a known pathogenic POLD1 variant. Details ▾Hide ▴
Evidence considered
- No phase data or co-occurrence data available.
Still missing
- No variant co-occurrence data.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002691.4:c.3046C>T is a missense substitution (p.Arg1016Cys), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The PVS1 decision framework (PMC6185798) does not apply to missense variants. Details ▾Hide ▴
Evidence considered
- Missense substitution in exon 24
- not a null variant class.
Sources
pvs1_variant_assessmentpvs1_gene_context
PM3 N/APOLD1-associated disease (PPAP) follows an autosomal dominant inheritance pattern; PM3 (in trans observation for recessive disorders) is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ANM_002691.4:c.3046C>T is a single-nucleotide missense substitution, not a protein-length-altering variant (in-frame deletion/insertion or stop-loss). Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable to confirm classic same-residue PM5 semantics; no pathogenic or likely pathogenic comparator variants at codon 1016 were identified in ClinVar. pm5_candidates.json confirms no eligible candidates. Details ▾Hide ▴
Evidence considered
- No same-residue comparator variants meeting PM5 criteria were identified.
Sources
pm5_candidates
BP1 N/APOLD1 is not a gene in which only truncating variants cause disease. Missense variants in POLD1 (particularly in the exonuclease domain) are a recognized disease mechanism in polymerase proofreading-associated polyposis (PPAP). Details ▾Hide ▴
Evidence considered
- POLD1 missense variants in the exonuclease domain are established as pathogenic in PPAP.
Sources
pvs1_gene_context
BP3 N/ANM_002691.4:c.3046C>T is a substitution, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_002691.4:c.3046C>T is a missense variant (p.Arg1016Cys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
PS5 N/APS5 is not a recognized criterion in the generic ACMG/AMP 2015 classification framework. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- POLD1
- Transcript
- NM_002691.4
- Coding (HGVS c.)
- NM_002691.4:c.3046C>T
- Protein (HGVS p.)
- NP_002682.2:p.(Arg1016Cys)
- GRCh38
- chr19:50416702 C>T
- GRCh37
- chr19:50919959 C>T
- ClinVar
- 537082, 408104
- COSMIC
- COSV113529574
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
9 / 1,541,950 alleles
AF 5.84e-06 · 0 homozygotes · FAF 1.78e-05
gnomAD v2.1
0 / 139,430 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5.8e-06 · 9 / 1,541,950 alleles · 0 hom · FAF 1.8e-05
| African/African American4 / 73,064 | 5.5e-05 |
| Remaining individuals1 / 59,968 | 1.7e-05 |
| European (non-Finnish)4 / 1,148,446 | 3.5e-06 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0 · 0 / 139,430 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD 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.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.321
- BayesDel
- -0.249
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.321 (benign range
- <0.5)
- BayesDel: -0.248952 (predicts benign)
- SpliceAI: max delta 0.00 (no splice alteration predicted)
Sources
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). No in silico evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.321 (not deleterious
- threshold typically ≥0.5)
- BayesDel: -0.248952 (predicts benign)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
BP7 N/ANM_002691.4:c.3046C>T is a missense variant (p.Arg1016Cys), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.321. BayesDel score = -0.248952.
3 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
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PMID 27149842 ↗Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma.Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma reports whole-exome sequencing of 619 incident CRCs identifying recurrently mutated genes. NM_002691.4:c.3046C>T (p.Arg1016Cys) was not identified in this paper.Does not name this variant
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PMID 29056344 ↗Comprehensive Analysis of Hypermutation in Human Cancer.Comprehensive Analysis of Hypermutation in Human Cancer assesses mutation burden across >81,000 tumors. POLD1 is mentioned at the gene level in the context of hypermutation. NM_002691.4:c.3046C>T (p.Arg1016Cys) 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.This ACMG/NSGC practice guideline provides referral indications for cancer predisposition assessment. It is a methods and policy document that does not report variant-specific observations. NM_002691.4:c.3046C>T (p.Arg1016Cys) 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
9 / 1,541,950 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
3 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/408104/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-50919959-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-50416702-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-50416702-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002691.4%3Ac.3046…
- OncoKB ↗www.oncokb.org/gene/POLD1/R1016C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=209466341
- 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= 5.83677e-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.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
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; COSV113529574, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.