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POLD1c.319C>TUncertain significance
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Variant interpretation report

POLD1 c.319C>T, p.(Pro107Ser)

NM_001308632.1:c.319C>T NP_001295561.1:p.(Pro107Ser) 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
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with rarity. Meets PM2 at supporting level under generic ACMG/AMP (allele frequency below 0.1% threshold).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence predict no deleterious effect. REVEL score is 0.015 (strongly benign-leaning; well below typical pathogenic threshold of 0.5), BayesDel score is -0.70 (benign-leaning), and SpliceAI predicts no splice impact (max delta score 0.01). GeneDx clinical submission also noted that in silico analysis supports no alteration of protein structure/function.

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.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

2 Uncertain significance · 1 Likely benign.

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
COSMIC ↗Cancer Hotspots ↗
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 · 21 not met · 1 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001308632.1:c.319C>T (p.Pro107Ser) is a missense variant in exon 3 of POLD1. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_supporting).

Multiple in silico predictors suggest a benign effect: REVEL score 0.015, BayesDel score -0.70, and SpliceAI max delta 0.01 predict no deleterious impact on protein function or splicing (BP4_supporting).

This variant has been reported in ClinVar (Variation ID 848162) as a Variant of Uncertain Significance by two clinical laboratories (Labcorp, GeneDx) and as Likely benign by one laboratory (Ambry Genetics). No expert panel review has been performed.

No variant-specific functional studies, segregation data, case-control analyses, or de novo reports were identified. OncoKB reports unknown oncogenic effect with no curated functional evidence.

Under generic ACMG/AMP 2015 combination rules, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in an overall classification of Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with rarity. Meets PM2 at supporting level under generic ACMG/AMP (allele frequency below 0.1% threshold). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles).
  • Absent from gnomAD v4.1 (0 alleles).
  • Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence predict no deleterious effect. REVEL score is 0.015 (strongly benign-leaning; well below typical pathogenic threshold of 0.5), BayesDel score is -0.70 (benign-leaning), and SpliceAI predicts no splice impact (max delta score 0.01). GeneDx clinical submission also noted that in silico analysis supports no alteration of protein structure/function. Details ▾Hide ▴
Evidence considered
  • REVEL 0.015 (strongly benign-leaning).
  • BayesDel -0.70 (benign-leaning).
  • SpliceAI max delta 0.01 (no predicted splice impact).
  • GeneDx ClinVar submission notes in silico analysis supports no alteration of protein structure/function.
Sources
revelbayesdelspliceai ↗

Not met · 21 · evaluated, threshold not reached

PS1 No evidence that a different nucleotide change at codon 107 resulting in the same Pro107Ser amino acid substitution has been classified as pathogenic. Details ▾Hide ▴
Evidence considered
  • No same-amino-acid pathogenic comparator identified.
Still missing
  • No ClinVar or literature data for alternate nucleotide changes yielding Pro107Ser.
PS2 No de novo occurrence data available for this variant. No parental testing or de novo confirmation reported in ClinVar submissions or literature. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PS3 No variant-specific functional studies identified. OncoKB reports unknown oncogenic effect with no curated functional evidence for this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB: unknown oncogenic effect
  • no variant-specific functional data.
Still missing
  • No functional assays performed on NM_001308632.1:c.319C>T (p.Pro107Ser).
Sources
oncokb ↗
PS4 No case-control or prevalence data establishing enrichment of this variant in affected individuals versus controls. ClinVar submissions represent isolated clinical observations without cohort-level statistics. Details ▾Hide ▴
Evidence considered
  • ClinVar VUS classification from 3 clinical laboratories
  • no case-control cohort data.
Still missing
  • No case-control or cohort prevalence studies available.
Sources
clinvar ↗
PM1 Residue 107 is not within a recognized mutational hotspot or well-established critical functional domain without benign variation. Cancer Hotspots analysis found no statistically significant clustering at this residue. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: residue 107 not significant
  • no pathogenic clustering at this position.
PM5 No pathogenic missense variant at the same amino acid residue (Pro107) identified in ClinVar. Automated PM5 candidate harvesting found zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense variants at Pro107 in ClinVar.
Sources
pm5_candidates
PM6 No de novo variant reports identified in ClinVar or literature. No confirmed de novo occurrence with maternity/paternity testing. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PP1 No cosegregation data available. No family studies or pedigree analysis reported for this variant. Details ▾Hide ▴
Still missing
  • No cosegregation or family data available.
PP3 Multiple computational predictors do not support a deleterious effect. REVEL score is 0.015 (strongly benign-leaning; threshold >0.5 for pathogenic), BayesDel score is -0.70 (benign-leaning; threshold >0.0 for pathogenic), and SpliceAI predicts no splice impact (max delta score 0.01). These do not constitute multiple lines of computational evidence supporting pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL 0.015 (benign-leaning).
  • BayesDel -0.70 (benign-leaning).
  • SpliceAI max delta 0.01 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No specific patient phenotype or family history data provided for assessment. Insufficient clinical information to evaluate phenotype specificity for a POLD1-associated condition. Details ▾Hide ▴
Still missing
  • No patient-level phenotype or clinical data available.
PP5 No reputable source classifies this variant as pathogenic. ClinVar reports Uncertain significance from 2 clinical laboratories (Labcorp, GeneDx) and Likely benign from 1 laboratory (Ambry Genetics). The classification framework paper cited by Labcorp (PMID:28492532, Sherloc) is a methods reference, not a source of variant-specific evidence. Details ▾Hide ▴
Evidence considered
  • ClinVar VUS: Labcorp (SCV001216040)
  • GeneDx (SCV001999651).
  • ClinVar Likely benign: Ambry Genetics (SCV002609124).
Sources
clinvar ↗
BA1 Allele frequency is 0% in gnomAD v2.1, v4.1, and gnomAD-Canada, well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases
  • AF = 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Allele frequency is 0% in gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases
  • AF = 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data on observation of this variant in healthy adult controls. Absence from gnomAD is consistent with rarity but does not constitute observation in confirmed healthy individuals. Details ▾Hide ▴
Still missing
  • No data on healthy adult carriers or full penetrance data.
BS3 No well-established functional studies demonstrating no deleterious effect of this specific variant. Computational predictors suggest benign impact but do not constitute functional assay evidence. Details ▾Hide ▴
Still missing
  • No variant-specific functional assays performed.
BS4 No nonsegregation data available. No family studies demonstrating absence of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No nonsegregation or family data available.
BP1 POLD1 disease mechanism includes both loss-of-function and missense variants. Pathogenic missense variants in the exonuclease domain are well-established in polymerase proofreading-associated polyposis (PPAP). POLD1 is not a gene where only truncating variants cause disease. Details ▾Hide ▴
Evidence considered
  • POLD1 disease mechanism includes both missense (exonuclease domain) and LOF variants
  • not a truncating-only disease gene.
Sources
pvs1_gene_context
BP2 No data on observation of this variant in trans with a known pathogenic POLD1 variant. Details ▾Hide ▴
Still missing
  • No phasing or trans-configuration data available.
BP5 No alternate molecular basis for disease identified in cases carrying this variant. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnoses in carriers.
BP6 No consensus benign classification from a reputable source. ClinVar reports mixed classifications: Uncertain significance (Labcorp, GeneDx) and Likely benign (Ambry Genetics). A single Likely benign classification without expert panel review does not meet the threshold for BP6. Details ▾Hide ▴
Evidence considered
  • ClinVar: 2 labs VUS
  • 1 lab Likely benign. No expert panel benign classification.
Sources
clinvar ↗
PS5 No family segregation data available. No multigenerational pedigree or linkage analysis data reported. Details ▾Hide ▴
Still missing
  • No segregation or family studies available.

Not assessed · 1 · no assessment recorded

PP2 HCI Prior scores are not available for POLD1. Cannot assess the rate of benign missense variation in this gene relative to pathogenic missense variation. Insufficient data to determine whether missense variants are a common mechanism of disease in POLD1. Details ▾Hide ▴
Evidence considered
  • HCI Prior data unavailable for POLD1.
Still missing
  • No HCI Prior or comparable missense constraint metric available for POLD1.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.319C>T, p.Pro107Ser) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Missense substitution at codon 107 (Pro→Ser)
  • not a null variant.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
BP7 N/AThis is a missense variant (c.319C>T, p.Pro107Ser), not a synonymous/silent variant. BP7 only applies to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution at codon 107
  • BP7 limited to synonymous variants.

Identifiers

Gene
POLD1
Transcript
NM_001308632.1
Coding (HGVS c.)
NM_001308632.1:c.319C>T
Protein (HGVS p.)
NP_001295561.1:p.(Pro107Ser)
GRCh38
chr19:50401780 C>T
GRCh37
chr19:50905037 C>T
ClinVar
848162

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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -328 bp
0.010
SpliceAI acceptor gainat -2 bp
0.000
SpliceAI donor lossat -262 bp
0.010
SpliceAI donor gainat -117 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.015
BayesDel
-0.700

How the predictions were used

BP4 SupportingMultiple lines of computational evidence predict no deleterious effect. REVEL score is 0.015 (strongly benign-leaning; well below typical pathogenic threshold of 0.5), BayesDel score is -0.70 (benign-leaning), and SpliceAI predicts no splice impact (max delta score 0.01). GeneDx clinical submission also noted that in silico analysis supports no alteration of protein structure/function. Details ▾Hide ▴
Evidence considered
  • REVEL 0.015 (strongly benign-leaning).
  • BayesDel -0.70 (benign-leaning).
  • SpliceAI max delta 0.01 (no predicted splice impact).
  • GeneDx ClinVar submission notes in silico analysis supports no alteration of protein structure/function.
Sources
revelbayesdelspliceai ↗
PP3 Multiple computational predictors do not support a deleterious effect. REVEL score is 0.015 (strongly benign-leaning; threshold >0.5 for pathogenic), BayesDel score is -0.70 (benign-leaning; threshold >0.0 for pathogenic), and SpliceAI predicts no splice impact (max delta score 0.01). These do not constitute multiple lines of computational evidence supporting pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL 0.015 (benign-leaning).
  • BayesDel -0.70 (benign-leaning).
  • SpliceAI max delta 0.01 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.319C>T, p.Pro107Ser), not a synonymous/silent variant. BP7 only applies to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution at codon 107
  • BP7 limited to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.015. BayesDel score = -0.699995.

1 paper record 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

  • 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. · 2015
    ACMG/NSGC practice guideline providing referral indications for cancer predisposition assessment. A general guideline document that does not discuss individual variants or genes. NM_001308632.1:c.319C>T (POLD1 p.Pro107Ser) was not identified in this publication.
    Does not name this variant
    PMID 25394175 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from 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 = 848162)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.015. BayesDel score = -0.699995.

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.