0%
POLD1c.2915C>TUncertain significance
Print report
Variant interpretation report

POLD1 c.2915C>T, p.(Pro972Leu)

NM_002691.4:c.2915C>T NP_002682.2:p.(Pro972Leu) View identifiers
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.

About POLD1

No gene-level summary was recorded for this case.

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
PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1 and observed at 0/1,552,088 alleles in gnomAD v4.1, which is below the 0.1% threshold used to support rarity in non-VCEP review. These data support that the variant is rare in population databases.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple computational results do not support a damaging or splice-altering effect. REVEL is 0.274, BayesDel is -0.220831, and SpliceAI shows a maximum delta score of 0.01, which is below a commonly used 0.20 threshold for significant splice impact.

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, BP4 supporting; combination = 1 moderate + 1 supporting benign, which maps to VUS because the evidence is conflicting.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 12 not met · 10 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The POLD1 c.2915C>T (p.Pro972Leu) variant has been reported in ClinVar as a variant of uncertain significance by one clinical laboratory.

This variant is absent from gnomAD v2.1 and has 0/1,552,088 alleles in gnomAD v4.1, which is below the 0.1% threshold used to support rarity.

Cancer Hotspots did not identify residue Pro972 as a statistically significant hotspot, which does not support application of PM1.

Available computational evidence does not support a damaging or splice-altering effect, with REVEL 0.274, BayesDel -0.220831, and SpliceAI maximum delta score 0.01.

Met · 2

PM2 ModerateThis variant is absent from gnomAD v2.1 and observed at 0/1,552,088 alleles in gnomAD v4.1, which is below the 0.1% threshold used to support rarity in non-VCEP review. These data support that the variant is rare in population databases. Details ▾Hide ▴
Rule
PM2_supporting_rarity_using_local_generic_thresholds; strength retained as PM2 in this generic ACMG pass.
Evidence considered
  • gnomAD v2.1: absent.
  • gnomAD v4.1: 0/1552088 alleles
  • AF 0.0
  • no homozygotes.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple computational results do not support a damaging or splice-altering effect. REVEL is 0.274, BayesDel is -0.220831, and SpliceAI shows a maximum delta score of 0.01, which is below a commonly used 0.20 threshold for significant splice impact. Details ▾Hide ▴
Rule
BP4 applied at supporting strength based on concordant computational evidence against a damaging effect.
Evidence considered
  • REVEL 0.274.
  • BayesDel -0.220831.
  • SpliceAI max delta score 0.01.
Sources
revelbayesdelspliceai ↗

Not met · 12 · evaluated, threshold not reached

PS2 No confirmed de novo occurrence with established maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar evidence does not document a confirmed de novo event for this variant.
Still missing
  • Published or laboratory-submitted de novo case data were not identified.
Sources
clinvar ↗
PS3 No well-established functional study for this exact variant was identified demonstrating a damaging effect on POLD1 function. Details ▾Hide ▴
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence.
  • Literature triage did not yield variant-specific functional data.
Still missing
  • Variant-specific validated functional assay data were not identified.
Sources
oncokb ↗PMID:28492532 ↗
PS4 This variant has not been shown to be significantly enriched in affected individuals compared with controls. Current evidence shows one ClinVar submission and no case-control enrichment data. Details ▾Hide ▴
Evidence considered
  • ClinVar reports one clinical laboratory submission.
  • gnomAD shows the variant is absent or at 0 observed alleles
  • but no case enrichment study was identified.
Still missing
  • Affected-case counts and formal case-control data were not identified.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM1 Available hotspot evidence does not support that residue Pro972 lies in a well-established mutational hotspot or critical region without benign variation. Cancer Hotspots did not identify this residue as a statistically significant hotspot. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots reported no hotspot row for POLD1 P972.
  • OncoKB provided only gene-level context and no variant-specific critical-region evidence.
Still missing
  • A residue-specific pathogenic clustering analysis outside the available hotspot resource was not identified.
Sources
hotspots ↗oncokb ↗
PM6 No assumed de novo occurrence without confirmation of maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar evidence does not document an assumed de novo event for this variant.
Still missing
  • Published or laboratory-submitted apparent de novo reports were not identified.
Sources
clinvar ↗
PP1 No segregation data were identified showing that this variant tracks with disease in affected relatives. Details ▾Hide ▴
Evidence considered
  • The available ClinVar record does not provide segregation evidence for this variant.
Still missing
  • Pedigree-level segregation data were not identified.
Sources
clinvar ↗
PP3 Available computational evidence does not support a deleterious effect. REVEL is 0.274, BayesDel is -0.220831, and SpliceAI shows a maximum delta score of 0.01, which is below a commonly used 0.20 threshold for significant splice impact. Details ▾Hide ▴
Rule
PP3 not applied because multiple in silico results do not support pathogenicity for this missense change.
Evidence considered
  • REVEL 0.274.
  • BayesDel -0.220831.
  • SpliceAI max delta score 0.01.
Sources
revelbayesdelspliceai ↗
BA1 Population frequency does not meet the benign stand-alone threshold. gnomAD v4.1 shows 0/1,552,088 alleles (0.00000%), which is below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AF 0.0 with 0 observed alleles.
Sources
gnomad_v4 ↗
BS1 Population frequency does not meet the benign strong threshold. gnomAD v4.1 shows 0/1,552,088 alleles (0.00000%), which is below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AF 0.0 with 0 observed alleles.
Sources
gnomad_v4 ↗
BS2 This variant was not observed in population databases in a manner that would support occurrence in healthy adults at a frequency expected for BS2. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • 0 observed alleles in gnomAD v4.1.
Still missing
  • Independent healthy adult carrier observations were not identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study for this exact variant was identified showing normal POLD1 function. Details ▾Hide ▴
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence.
  • Literature triage did not yield variant-specific normal-function data.
Still missing
  • Variant-specific validated functional assay data demonstrating no damaging effect were not identified.
Sources
oncokb ↗PMID:28492532 ↗
BS4 No non-segregation data were identified showing that this variant fails to track with disease in a family. Details ▾Hide ▴
Evidence considered
  • The available ClinVar record does not provide non-segregation evidence for this variant.
Still missing
  • Unaffected-carrier or non-segregation pedigree data were not identified.
Sources
clinvar ↗

Not assessed · 10 · no assessment recorded

PS1 No evidence was identified showing that this same amino acid change, p.Pro972Leu, has already been established as pathogenic through a different nucleotide change. Details ▾Hide ▴
Evidence considered
  • ClinVar currently shows a single VUS submission for this exact variant
  • not an established pathogenic equivalent amino acid change.
Still missing
  • A codon-level review for alternate pathogenic nucleotide changes encoding p.Pro972Leu would be needed.
Sources
clinvar ↗
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disorder context. Details ▾Hide ▴
Still missing
  • Phase data and recessive-case observations were not identified.
PM5 No evidence was identified showing a different pathogenic missense change at codon 972 that would support PM5. Details ▾Hide ▴
Evidence considered
  • ClinVar evidence available for this case does not establish another pathogenic missense change at this codon.
Still missing
  • A codon-specific review for other pathogenic substitutions at Pro972 would be needed.
Sources
clinvar ↗
PP2 Available evidence for this case does not establish that POLD1 is a gene in which missense variation is a sufficiently common and well-supported disease mechanism to apply PP2 for this variant alone. Details ▾Hide ▴
Evidence considered
  • Gene-level review addressed loss-of-function eligibility
  • not PP2 missense calibration.
Still missing
  • Gene-level missense mechanism calibration for PP2 was not provided in the available sources.
Sources
pvs1_gene_context
PP4 No phenotype or family-history information was provided that is highly specific for a single genetic etiology and attributable to this variant. Details ▾Hide ▴
Still missing
  • Detailed clinical phenotype data were not available for phenotype-specific assessment.
PP5 No reputable-source pathogenic assertion was used without access to the underlying evidence. The available ClinVar record is a single-submitter VUS and does not support PP5. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance
  • single submitter.
Sources
clinvar ↗
BP1 Available evidence does not establish that POLD1 is a gene in which truncating variants are the primary disease mechanism such that a missense variant would favor BP1. Details ▾Hide ▴
Evidence considered
  • Gene-level review supports loss-of-function eligibility but does not justify BP1 use for this missense variant.
Still missing
  • Gene-level benign weighting framework for BP1 was not available.
Sources
pvs1_gene_context
BP2 No phase information was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that would support BP2. Details ▾Hide ▴
Still missing
  • Phase and co-occurrence data were not identified.
BP5 No alternate molecular diagnosis or other clearly explanatory variant data were provided to support BP5. Details ▾Hide ▴
Still missing
  • Case-level alternate diagnosis data were not available.
BP6 No reputable-source benign assertion was used without access to the underlying evidence. The available ClinVar record is a single-submitter VUS and does not support BP6. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance
  • single submitter.
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, NM_002691.4:c.2915C>T (p.Pro972Leu), and it does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Although gene-level review supports that loss of function can be a disease mechanism in POLD1, the generic PVS1 scaffold does not support applying PVS1 to this amino acid substitution. Details ▾Hide ▴
Rule
Generic PVS1 fallback withheld because the variant is not a null-variant class eligible for PVS1.
Evidence considered
  • POLD1 loss of function is considered an eligible mechanism at the gene level.
  • The exact variant is a missense substitution rather than a predicted null variant.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM4 N/AThis criterion applies to protein length changes from in-frame insertions/deletions or stop-loss variants, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Variant consequence is p.Pro972Leu missense.
BP3 N/AThis criterion applies to in-frame indels in repetitive regions without known function, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Variant consequence is p.Pro972Leu missense.
BP7 N/AThis criterion applies to synonymous variants with no predicted splice impact, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Variant consequence is p.Pro972Leu missense.

Identifiers

Gene
POLD1
Transcript
NM_002691.4
Coding (HGVS c.)
NM_002691.4:c.2915C>T
Protein (HGVS p.)
NP_002682.2:p.(Pro972Leu)
GRCh38
chr19:50416490 C>T
GRCh37
chr19:50919747 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…
gnomAD v4.1 0 / 1,552,088 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,552,088 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= 0; MAF= 0.00000%, 0/1552088 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73292 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMultiple computational results do not support a damaging or splice-altering effect. REVEL is 0.274, BayesDel is -0.220831, and SpliceAI shows a maximum delta score of 0.01, which is below a commonly used 0.20 threshold for significant splice impact. Details ▾Hide ▴
Rule
BP4 applied at supporting strength based on concordant computational evidence against a damaging effect.
Evidence considered
  • REVEL 0.274.
  • BayesDel -0.220831.
  • SpliceAI max delta score 0.01.
Sources
revelbayesdelspliceai ↗
PP3 Available computational evidence does not support a deleterious effect. REVEL is 0.274, BayesDel is -0.220831, and SpliceAI shows a maximum delta score of 0.01, which is below a commonly used 0.20 threshold for significant splice impact. Details ▾Hide ▴
Rule
PP3 not applied because multiple in silico results do not support pathogenicity for this missense change.
Evidence considered
  • REVEL 0.274.
  • BayesDel -0.220831.
  • SpliceAI max delta score 0.01.
Sources
revelbayesdelspliceai ↗
BP7 N/AThis criterion applies to synonymous variants with no predicted splice impact, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
  • Variant consequence is p.Pro972Leu missense.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.274. BayesDel score = -0.220831.

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 0 / 1,552,088 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

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= 0; MAF= 0.00000%, 0/1552088 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73292 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.274. BayesDel score = -0.220831.

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.